Drug Distribution
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What is drug distribution?
Dispersion of a drug among fluids and tissues of the body
Where can the drug actually go?
From the dose, it will enter circulation/blood vessels and can then go to outside blood vessels or into well perfused areas and then poor-perfused areas. There is an equilibrium between: [drug] in blood <—> [drug] at site of aciton
What are examples of extravacular space?
Adipocytes, skeletal muscle
What are some pharmacokinetic parameters?
• Drug half-life • Volume of distribution • Bioavailability • Elimination process / Clearance
What happens in first-order kinetics?
• Exponential decay in rate • Constant half-life • Constant fraction of drug being removed • No saturation point of transporters involved in elimination
If the dosage of the drug is increased, what happens with first-order kinetics?
Nothing changes - the same constant fraction is removed, and constant half life remains same.
Do most drugs obey first-order or zero-order kinetics?
First-order
What happens in zero-order kinetics?
• There is a fixed rate, so absorption/distribution/elimination processes are saturated • Constant AMOUNT of drug is removed • The bigger the dose the longer the time to remove it • Unpredictable kinetics and can lead to toxicity eg. alcohol
What is the volume of distribution (Vd)?
Total amount of drug / [plasma] = Apparent volume of distribution Tells you how much of the drug is in vascular space/indicates distribution, if Vd high then some drug outside vascular space. Clinically important for adjusting dosage
What is meant by plasma clearance?
It is how quickly our body removes the drug - the volume of plasma cleared of drug per time (ml min-1). It’s a constant for 1st order reactions
What is bioavailability?
F = The fraction of drug in circulation compared to dose (measures extent of absorption). For IV, F = 1 always. Oral, F = 0.1 (10% bioavailability) so need to increase dose by x10
Give reasons for low bioavailability
• Poor absorption • Chemical reactions at site of delivery • First-pass metabolism
What is the point of multiple dosing?
• Achieve a ‘steady state’ • More doses before [drug] falling to zero - to allow buildup • [drug] variation depends on half-life + dose interval
What does the dosage regime balance?
Dosing rate = rate of elimination
What is the equation for dosing rate and target concentration?
Dosing rate x F = CF x Target concentration (Css) (example calculation on powerpoint)
Repeated doses of drug eventually produce a steady state concentration, true or false?
Tru
How long is the time to plateau (steady state)?
4-5 x drug half life
Steady state levels are flat, true or false?
False
Why are fluctuations bad?
Create potential for sub-therepeautic treatment or toxcitity
Will increasing the number of daily doses decrease or increase fluctuations?
Decrease
For drugs with long half lives, achievement of steady stte can be accelerated by a loading dose. What is a loading dose?
Loading dose is a much bigger initial dose to bring concentration up to steady state, then smaller maintenance dose is given to maintain the desired level in the long run.
Will changing the rate of drug infusion change the time required to reach steady-state?
No - Time required to reach steady state is independent of the dose. Only the concentration of steady state changes, but time/rate remains same (4-5 half life).