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.
How are drugs partitioned into tissues?
Lipophilic drugs into fat
i.e chloroquin, may lead to dosing problems in obese patients where fat content is much higher
Drug adsorption onto bone
- i.e Bisphosphonates
Compare and contrast warfarin and gentamicin v of distribution:
Warfarin ~10L
- Less than ECF, larger than plasma volume
- Highly plasma protein bound
i. e huge red herring effect
Gentamicin ~16L
- Similar to ECF
- Highly ionised, low plasma protein binding
i. e Indicates that it doesnt not bind extensively to tissues
Compare and contrast theophylline and digoxin v of distribution:
Theophylline v ~35L
- Similar to total body water
- Non polar, low plasma protein binding
i. e non polar so is expected to cross cell membranes, its apprent v is similar to total body water which suggests it does not bind extensively to tissues
Dixogin ~500L
- Na/K ATPase binding
- Muscle, Kidney, Nervous tissue
i. e very large apparent V, negligible binding to protein, but high affinity and binding to tissues.
What are the pharmacokinetic compartments? i.e the time course of a drug related to its compartments
Apparent central compartment volume
- Instantaneous distribution
Apparent tissue compartment volume
- Delayed distribution
- Depends on tissue binding and partitioning
Describe how drugs move through the compartments:
Drug distributes through the plasma and then out into the ECF space and then onto the cells. This process takes time and so the apparent volume of distribution will change with time. Steady state will occur when volume no longer changes with time.
For simplicity it is common to consider one or more pharmacokinetic compartments representing drug distribution at some point in time. The central compartment reflects the initial rapid distribution while the tissue compartment reflects the space after sufficient time has passed to reach steady state of distribution
What is the use of the one compartment model:
Explains the instantaneous distribution
- can be just plasma or can be through whole body
- Uses first order elimination (as drug not distributing into other compartments)
What is the use of the two compartment model:
Central compartment joins peripheral compartment
- Initial volume of distribution and initial concentration is same as one compartment model (reflecting the instantaneous distribution), but, over time it can distribute into the second compartment and a steady state is achieved. ( thus new steady state V but concentration falls over time)
What is importance of V?
- Can be used to calculate loading dose (MAIN USE)
- > Time to reach steady state
- > Time for all the drug to be eliminated
- V does not influence the steady state conc (Css)
- Css is determined by
- > Clearance of the drug
- > rate of input
What is a loading dose and what is it dependent on?
Initial dose administered to achieve a target concentration rapidly
- Dependent on v
- Helps fill bath (v) faster to rapidly achieve the target concentration
- The bigger the V the higher the dose required to achieve target concentration
What is the equation for loading dose?
Loading dose (mg) = V (L) x target concentration (mg/L)
What happens if no loading dose is used?
If no loading dose is used, the volume takes time to fill up, so the larger the V the longer the time it takes to reach target concentration
Loading dose usually given as IV infusion, oral dosing can also be used.
