Volume of distribution Flashcards
What is the extent of distribution defined by?
Apparent volume of distribution (Vd), based on equilibrium concept
What does the volume of distribution equal?
V = A/C
A - Amount of drug in the body at equilibrium
C - measured plasma drug concentration
Why might the same dose for 3 different drugs achieve very different plasma concentrations?
All 3 drugs have different volumes of distribution
What is the apparent volume of distribution (Vd) equal to?
Vd = (Amount of drug in the body at equilibrium)/(Drug concentration in the plasma)
What is apparent volume of distribution?
The apparent volume that the drug occupies at a concentration equal to that in plasma.
*note: refers to not a physical but an APPARENT volume. The value depends on the reference fluid measured (plasma, blood, plasma water (unbound drug conc)
What is the approximate value of plasma water in the body?
3L
What is the approximate value of extracellular water in the body?
12L
What is the approximate value of the total body water?
40L
At equilibrium what does the amount of drug in the body (A) equal?
A=V.C=Vb.Cb=Vu.Cu
amount=plasma=blood=plasma water
What does the volume of distribution NOT tell you?
WHERE it has been distributed
What Volume of distribution do mAbs have?
Very low volume of distribution - reside in the plasma
What volume of distribution do acidic drugs (warfarin, tolbutamide) tend to have?
Acidic drugs are highly ionised and bind to plasma proteins extensively so generally have a low volume of distribution
What volume of distribution do basic drugs (fluoxetine) tend to have?
High volume of distribution - accumulate in tissues and bind to acidic phospholipids
What does the fraction of drug in body in plasma equal?
= Vp/V
Vp - plasma volume (3L)
*note both are multiplied by C but cancel each other out
What is the relationship between the volume of distribution and fraction of drug in the plasma?
The higher the volume of distribution, the fraction in the plasma is smaller
What does the fraction of drug in body outside of plasma (including blood cells) equal?
= V-Vp/V = 1-Vp/V
What are lysosomes?
Acidic organelles (pH 4-5)
Describe lysosomal trapping:
- A basic unionised drug crosses the membrane into cytosol (pH 7-7.4) and gets into the lysosome
- Because the pH is more acidic, the basic molecule will become ionised
- Protonated form becomes the DOMINANT form
- Protonated form cannot diffuse back into the cytosol
*SUBCELLULAR DISTRIBUTION
What organs/tissues have a large proportion of lysosomes?
Macrophages in the lungs and liver
In what case is lysosomal trapping beneficial?
For antimalarial drugs (e.g. chloroquine), they target the lysosomes of particular cells
Generally, is lysosomal trapping good or bad?
Generally bad, as we want effects in the cytosol, not the lysosome. E.g. antibiotic resistance linked to extensive accumulation in the lysosomes
What is a safety concern for lysosomal trapping?
Phospholipidosis - extensive accumulation in lysosomes
What protein do acidic drugs bind to?
Albumin
What protein do basic drugs bind to?
alpha1 - Acid glycoprotein
What do steroids bind to?
globulins
What is fu?
Fraction of drug unbound in plasma
How do you work out fraction of drug bound?
1-fu
What does fu depend on?
o Affinity of the protein for the drug defined by the dissociation constant (Ka)
o Protein and drug concentration
Why is knowing fu important?
- When fu is constant, changes in TOTAL plasma concentration reflect changes in the UNBOUND drug calculation (C=Cu/fu)
