L16. Timecourse of Delayed drug effects Flashcards
What is considered a delayed drug effect and what are the three main processes that lead to it
A delayed drug effect is when drug effects are delayed in relation to plasma drug concentrations.
This is due to time taken for
1. Distribution to effect site (receptor)
2. Binding to and unbinding to receptor
3. The drug action to change physiological intermediate substances
What is the difference between pharmacokinetic and physiokinetic models for delayed drug response
The Distribution to effect site is determined by pharmacokinetics. This is usually short (min). Whereas Turnover of physiological mediator of effect is determined by physiokinetics and this can be long (hours+).
What determines the rate of accumulation to steady state of thiopentone in the Plasma compartment vs the Effect compartment when the input is constant
- The accumulation of drug in plasma
is determined by the half life of elimination = 0.7 x V/CL - Time course of accumulation of drug conc to reach steady state is determined by a constant rate input from blood and by the half life of loss of thiopentone from the brain (equilibration half life)
What is the effect compartment vs plasma compartment
Plasma compartment = conc of drugs in plasma
Effect compartment = conc of drug at receptor site responsible for effect and is worked out through measuring equilibration half life.
Define Equilibration half life and what are the two factors which influence it
The time course of equilibration between plasma and effect compartments, influenced by:
- Volume of effect compt. (organ size, tissue binding)
- Clearance of effect compt. (rate of blood flow and diffusion rate from delivery system to effect site)
Why does Thiopentone (anaesthetic) have a delayed drug effect
Distribution to effect Site (brain): from the blood (central compartment) across blood brain barrier, through ECF fluid spaces in the brain to GABA receptor site (effect site) causes delay.
Also: Equilibration half life is short (1min)
Why is Thiopentone’s time equilibration half life short
Time course of the binding is determined by the half life (of elimination and equilibration)
Half life of equilibration is short because Vd is small because limited binding to GABA receptors and there is high CL because rapid perfusion of the brain
Why does Digoxin have a delayed drug effect
Delayed onset of digoxin effects is due to the Slow unbinding from NaKATPase which causes the heart to take a long time to reach binding equilibrium because of long dissociation half life.
Also equilibration half life is slow
1. There is a large volume of distribution (due to extensive binding in heart to NAKATPase).
2. Despite rapid perfusion of heart so CL is high
Why is digoxin considered to be a potent drug
Its long dissociation half life means that the concentration producing 50% of full receptor binding at equilibrium will be small and this the potency of drug is high
What is the drug action, rapid effect and delayed response (measured) of Warfarin
- Drug action (fast) inhibition of Vit K recycling
- Rapid effect: decreased synthesis of clotting factors in the liver
- Delayed response: prolonged coagulation time (measured by INR , high = less clotting= good)
How does change in C50 value for warfarin inhibition of Vit K recycling (due to genetic differences) affect its INR if concentrations stay at average 1.5 mg/L
Normally
C50= 1.5 mg/L which is average conc. This just leads to half conc of clotting factors and therefore doubles INR= 2
If more sensitive: C50 lower (0.75). INR goes up to 3.
If less sensitive: C50 higher (3) then INR =1.5
Why does Warfarin have a delayed response and what factors contribute to the level of response
The time to reach a new steady state INR is determined by the half life of prothrombin complex (~14hr) so it takes 2/3 days to reach steady state.
VS
How much the INR changes depends on the C50 for warfarin inhibition of vit K (and conc of drug).
What does a cumulative drug response mean, how is it generally calculated and give an example
The benefit of the drug action is directly related to the cumulative exposure to the drug.
eg. Benefit of diuretic frusemide is from the net amount of water excreted through excretion of Na+
Calculated from the area under curve of effect vs time graph.
What is schedule dependence
Despite the overall dose - concentrations delivered being the same, giving smaller doses more frequently can increase the total area under the effect vs time graph (because effect and conc have non linear relationship) and therefore increase overall response by 50%.
This happens because there is no saturation of receptors at smaller doses.
What type of drugs show schedule dependence vs not
Despite having cumulative response,
Drugs with reversible binding show schedule dependence because it can approach maximum after each dose.
Whereas Drugs that Irreversibly bind do not show schedule dependence - eg. anti-cancer agents, response only depends on actual dose.
