Lecture 15: Time Course of Delayed and Accumulative Drug effects Flashcards
Pharmacokinetic delay in drug respose?
Distribution to effect site that is not in the blood (central compartment) driven by th rapidly mixing blood volume
eg. Thiopentone an anaesthetic must pass the BBB
- delays in perfusion time
- delays in diffusion across blood vessels walls and through extracellular spaces
Pharmacokinetic delay number 2?
Determining factors?
Equilibration half-life
It is the time needed to reach a steady state in a pharmacokinetic system recieving constant rate input determined by the elimination half-life from the plasma compartment.
- Volume of effect compartment (organ size, tissue binding)
- Clearance of effect compartent (blood flow, diffusion)
Receptor-kinetics delay in drug reaponse?
Binding to and unbinding from receptor
- drugs usually bind quickly to the receptor but dissociate slowly
- equilibrium receptor binding is determined by the ratio of association half-life and dissociation half-life
- a long dissociation half-life means that the conc producing 50% of binding at equilibrium will be small = high potency.
Physio-kinetics?
Physiological intermediate
It takes time for a drug to actually change the physiological intermediate and cause a drug response that is observable.
Thiopentone delayed response?
Anaesthetic
Short equlibration half-life (1 min) based off : small volume as limited binding to GABA and quick clearance due to rapid perfusion and high blood flow of the brain
Digoxin delayed response?
Slows AV conduction and increases heart contractility
Has a long Equilibriation half-life:
- large volume (extensive binding to Na/K ATPase and also long dissociation half-life)
- quick clearance due to rapid perfusion and so doesn’t compensate.
Because of its long dissociation half life it is very potent (used in nanomolar concentrations)
Delayed response of warfarin?
Warfarin inhibits the recycling of Vitamin K which has a rapid effect of decreasing production of clotting factors.
The delay comes from the long elimination half-life (14h) of the prothrombin complex of clotting factors. Mesured by a prolonged coagulation time (INR) that takes 2-3 days/4 half-lives to reach a new steady state.
Synthesis is reduced 50% and C50 of 1.5mg/L but the time to steady state is independent of how much is given becuase it is off the depletion half-life
Schedule dependence?
A dose-response that can be predicted using PKPD models and then observed clinically
For any drug dose given over a period of time, the total drug effect will depend on the dosing schedule. This is particulary important for drug that show reversible binding properties at the site of action
It is a result of the non linear relationship between effect and concentration.
Cumulative drug response seen with ______?
explain
Furosemide
Has a Hill co-efficient of 3
The effects starts quickly and reaches a plateau at about 90% for two hours before dropping away wuite quickly. Here the loss of effect curve is steeper than the loss of plasma concentration due to the H = 3
When 40g is given instead of 120g the max effect is only slighty decreased but duration is similar. AUCe can be used to calculate effect
3x 40g = 600mmol Na+/12h
1 x 120g = 400mmol Na+/12h
Irreversible anti-cancer agents? cummulative dose response?
No need. If they bind permanently then you just give it all at once. Show NO schedule dependence
Dose individualisation?
Busulfan is used to ablate bone marrow before a transplant.
The response is due to cummulative exposure (AUC) so must check plasma conc after first dose to guide treatment avoiding toxic overdose.
