Lecture 5: Volume of distribution Flashcards
What is drug distribution:
The reversible movement of drug between body compartments once it has entered the systemic circulation. (drugs need to reach tissues to have effect, thus need to be able to leave circulation)
Defined by: Volume of distribution (V)
What influences the physicochemical properties of drugs and thus their ability to cross plasma membranes:
- Size
- Ionisation
- Lipophilicity
- Plasma protein binding
What does tissue concentration indicate?
Tissue concentration indicates drug effectiveness because this is where it acts. However, we cant measure tissue concentration thus we must infer it; Volume of distribution
What is the formula for volume of distribution?
V = amount of drug in body / plasma drug concentration
What are the determinants for volume of distribution?
- Body mass and composition
- Tissue blood flow
- Tissue binding (increase V)
- Plasma protein binding (decrease V)
- Physicochemical properties of the drug
- Natural barriers i.e BBB
What does V link? is it useful?
APPARENT volume of distribution links drug concentration to the amount of drug in the body.
While the volume may be similar to a physical space in the body, it is not necessary to assume that the apparent volume corresponds to a physiological volume
How can the bathtub be used to describe volume of distribution?
Dose of drug into a bathtub, you can measure the concentration and infer the apparent volume of distribution
Describe practically the volume of distribution regarding the plasma:
The volume that the drug must be dissolved in to give a concentration equivalent to that found in the plasma.
- Gives an indication of distribution out of the plasma into the tissues
- v = amount / conc. plasma
Why is volume of distribution not a physiological value?
Total body water in a 70kg person = ~42L
- Blood ~5L and plasma ~3L
- ECF ~14L, ICF ~ 28L
v can exceed 42L i.e chloroquin is >10,000L
Drugs that rapidly distribute to tissues will have high V
Drugs that stays in plasma will have low V
What makes v not physiological? 3 things
- Binding to tissues
- > have high V
- > i.e Digoxin binds Na/K ATPase
(i.e the apparent volume is larger because the concentration of plasma is lower as drug is bound to the tissues and decreases the plasma concentration)
- Binding to plasma proteins
- Partitioning into tissues
Describe drug binding to plasma proteins and how this changes v:
- V is misleading
- > Bound drug is pharmacologically inactive
i. e Warfarin to albumin, imatinib to alpha 1 glycoprotein
So the drug will be measured in the plasma producing a smaller volume of distribution.
Describe how warfarin changes V:
Warfarin is 99% bound to albumin and 1% unbound.
Therefore depending on which measure is used in V calculations, v can vary from 10L (bound) to 1000L (unbound)
BUT very hard to measure unbound so often total drug conc. used. Plasma protein binding fraction usually remains constant. In which case it doesnt matter.
Whats the clinical relevance of plasma protein binding:
- Approx 50% drugs are >90% bound to plasma proteins, thus unbound drug concentrations are responsible for effects
Does altering plasma protein binding impact clinically?
i. e by displacement with competing drug or through disease
- > Increase elimination of unbound drug i.e metabolism (rarely changes clinical response)
- > No change in steady state unbound drug concentration most of the time (because of the aforementioned elimination)
In what instances may changes in the bound drug concentration be clinically impactful?
- Rapidly cleared IV drugs that are highly plasma protein bound with a narrow therapeutic index window rarely can cause issues when bound conc. is changed.
