Volume of distribution Flashcards
What is the definition of volume of distribution?
The apparent volume of distribution describes the relationship between the the concentration of the drug and the amount of drug in the body.
Note: it is an ‘apparent’ volume of distribution so it shouldnt be assumed to an actual physical volume, but it should be close to the physical volume.
How do you calculate loading dose?
If you know the target concentration you want to achieve in the body and you know the apparent volume of distribution then the loading dose can be calculated.
LD = target conc (mg/L) x volume (L) LD = \_\_\_\_ mg
Using the bathtub model explain how apparent volume of distribution can be measured?
In a full bathtub with the tap off and plug in - if you know the concentration of drug you put in and then measure the concentration of the drug in the bathtub then you can determine apparent volume of distribution.
What are the three main factors that mean apparent volume of distribution does not necessarily correspond to any physical compartment such as vascular volume of exracellular fluid volume?
- Binding to tissue
- Binding to plasma proteins
- Partitioning into fat or absorption onto bone
Name a drug that illustrates tissue binding and what this means in terms of the apparent volume measured?
Digoxin is a drug that binds extensively to tissue - it binds to Na/K/ATPase enzyme. Na/K/ATPase is espeshially found in the muscle, brain and kidney.
This means that when the conc of the drug is measured in the blood it will be lower than what it would be if it was uniformly distributed in the blood. (think of it like the enzyme acting as a sponge in the bathtub).
This means the apparent volume of distribution will be large (as for the conc to be so low it must have spread over a large volume - but in this case it “tricks” the measurement by just being bound to the tissue enzyme).
Therefore tissue binding results in an apparent volume of distribution larger than the physical volume.
Name some drugs that have larger apparent volumes of distribution due to partitioning?
Some drugs are lipophillic (like fat) and so will partition more into fat. eg thiopentone. This means that in obese people they often have a very large volume of distribution for a lipophillic drug. A drug that is hydrophillic will have no effect on the apparent volume of distribution.
Some drugs can be absorbed into bone. Biphosponates are a type of drug that absorb into bone and this is particularly helpful for people with bone diseases like osteopoerosis. Tetracylcine is another bone absorbing drug and this can make childrens teeth stain. Both of these drugs will result in a larger apparent volume of distribution.
Name a drug that extensively binds to plasma protein and what this means in terms of calculating what dose to give?
Warfarin is a drug that binds extensively to plasma proteins (about 99% is bound).
Thus when a sample of blood is taken to measure the conc of warfarin will be higher in the sample compared to the rest of the blood as it will measure the conc in the water as well as what is bound/concentration in the plasma proteins.
If the total drug conc in the blood was measured this would mean the apparent volume of distribution would be tiny (10L approx) whereas if just unbound was measured it would be huge (approx 1000L).
This poses a difficulty when trying to calculate the loading dose to give someone, espeshially as measuring the unbound conc (whats floating in the plasma water/fluid) is hard and exspensive. (measuring unbound is the best as it is only the unbound conc that is pharmacologically active). The way to get around this is to just measure total conc to calculate apparent volume of distribution and then calculate target conc based on the total conc you want t achieve. (So as long as volume and target conc are in the same terms).
The small apparent volume of distribution is described as a ‘red herring’ effect as a red herring is something that is ‘misleading’.
Why is unbound druug concentration the only thing that should be considered pharmacologically?
Unbound is the only drug to be metabolised in the blood it is the only to cause an effect on the target tissue and it is the only drug that is pharmacologically active. It is also the only drug that can be eliminated by the kindey - albumin cant be filtered through the glomerulus.
Would taken ibuprofen whilst on warfarin cause much of an effect on the action of warfarin?
Ibuprofen can displace warfarin from the plasma proteins. However, of all the drug in the durg (for warfarin usually 10mg), only 25% s actually in the plasma. (plasma proteins are only a small part of the tissue that binds warfarin). Ibuprofen can only displace 10% of this 25% and therefore there will only be an increase of 2.5% in the unbound (pharmacologically active) warfarin and so this will have a neglilgible effect.
This will mean steady state will remain pretty much the same as long as the drug like ibuprofen dosent effect the clearance from the liver or that the maintence dose dosent change.
What is the apparent volume of warfarin? (blood thinner)
10L
- small due to plasma protein binding
- (less than ECF but greater than plasma volume)
What is the apparent volume of gentamicin? (antibiotic)
18L
- highly ionised moleculae that dosent cross cell membranes therefore it remains in the plasma and so its apparent volume is quite close to physical volume of ECF.
- this indicates it does not bind extensively to tissue
What is the apparent volume of theophylline? (beta antagonist - allows for relaxation/vasodilation).
35L
- it isnt particularly polar so will cross cell membranes
- however, we know it dosent bind to plasma proteins and its apparent volume is close to total body water so this indicates it probs dosent bind to tissues extensively either
What is the apparent volume of digoxin?
500L
- it has negligible binding to plasma proteins but binds extensively to Na/K/ATPase containing tissues and these are found in just about every cell so this is why its apparent volume is so large
Why do you have to be careful with the dose of digoxin you give elderly, obese and those with kidney failure?
Digoxin binds extensively to Na/K/ATPase and this is found in high abundance in muscles and the kidney.
In elderly they have low muscle mass compared to their body weight and so they will have a smaller volume of dis as there is less muscle tissue for the drug to bind to so more in the plasma.
The same deal goes for obese people.
For people with chronic kidney failure their kidneys often shrink and so there is less kidney mass for the drug to bind to so a lower apparent volume of dis as more in the plasma.
Why is the time course of drug distribution important to consider?
This is mainly only important to consider for anaesthetics as they need to know drug conc int he body rapidly.
Immediately after a drug is put in the body it is distributed in the plasma volume and then after some time it will move into the extracellular fluid and then into cells. The mixing of the drug in the plasma fluid and then moving into ECF takes some time and so the volume of distribution increases over time.
central compartment - reflects the intial rapid disrribution of the drug in the plasma
tissue compartment - reflects the space the drug is occupying after sufficient time has passed to reach steady state of distribution
Is considering a two compartment model (imagine to connecting beakers with the drug being administered in one), what happens to the apparent volume of distribution?
Initially all of the drug conc will be in the first beaker (initial volume of dis will be determined by this) but over time the drug will redistribute into the second beaker and so there will be a drop in conc but will soon reach steady state as the drug moves back and forth between the two compartments.
When this is coupled with elimination (at same rate as fluid is entering) the volume will stay the same but the conc will fall.
What are the relative distributions of thiopentone (anasthetic), digoxin and lithium?
Thiopentone = rapid (minutes) This is fast acting as it quickly distributes to the brain but then soon after redistributes to the body which causes a loss of effect
DIgoxin = moderate (hours) Apparent volume of dis takes a long time to reach steady state as binding to Na/K/ATPase takes some time
Lithium = slow (days) Takes a long time to reach steady state as it must exchange slowly with sodium inside cells.
