Lecture 5

Question 1

Define volume distribution?

Answer 1

The relationship between concentration and the amount of drug in the body.

Question 2

What is loading dose?

Answer 2

This is the first dose given to achieve the target concentration. The amount of drug we need in the body. Unit is mg.

Question 3

Describe the bathtub model in terms of volume distribution?

Answer 3

Putting a known amount of drug into the bathtub and measuring the concentration you can measure the apparent volume. However the body isn’t a bathtub, when we work out the volume it isn’t necessarily the physical volume it is the apparent volume.

Question 4

What is the problem with drugs in terms of volume distribution?

Answer 4

Drugs typically bind to tissues, commonly they bind to proteins.

Question 5

Describe the sponge model in terms of volume distribution?

Answer 5

If we put digoxin into the bathtub, the water binds tightly to the sponge. Then most of the drug will be in the sponge. Most of the drug is in the sponge and not in the bathwater. So when we measure the concentration on the bathwater, it will be much lower because most of the drug is in the sponge. Therefore the apparent volume distribution will be larger than it really is (as volume distribution is inversely proportional to concentration).

Question 6

What is the problem with tissue binding?

Answer 6

The problem is that the apparent volume has increased (i.e. with dogixin it has increased to 350L), however the physical volume is actually the same. This is because we are only measuring the concentration in the blood, yet we do not know what is happening to the tissues.

Question 7

What is drug partitioning?

Answer 7

Drugs which are lipophyilic (i.e. thiopentone) will have a volume distribution will be determined by the amount of fat on the body. this is due to tissue binding. Bone is not a big contributor to volume distribution. However, tetracycline binds slowly to bone (don’t use in children as it binds to their bones - children would get growth rings in their teeth and slightly green). the children have not finished their bone growth; whereas adults have. However, adults are at risk of osteoporosis when you get older, the drug bisphosphonates will kill osteoclasts (the bone doesn’t breakdown - bone mass increases). they work by binding to the bone, the volume distribution is big as there is lots of bone to bind to. Radioactive caesium, binds to bone and can cause cancer (bone tumours).

Question 8

Describe plasma protein binding?

Answer 8

Some drugs with weak acids (warfarin) and weak bases (lignocaine) will bind to plasma proteins (such as albumin and alpha 1-acid-glycoprotein). Because plasma is the quantity that you will use to measure the drug concentration, the concentration will appear bigger due to the drugs binding to these plasma proteins. Thus the volume distribution will appear smaller. This is known as a Red Herring.

Question 9

Describe the red herring model in terms of volume distribution?

Answer 9

The drug binds to plasma proteins, when we do our experiment to determine volume distribution, a lot of the concentration will get bound to the red herring. You will then take a sample of the bath water with the red herring as well, thus the drug concentration will be larger (bath water + red herring). Because the drug concentration has apparently increased, thus there will be a small volume distribution. the apparent volume will be smaller than the physical volume.

Question 10

Describe warfarin as a red herring?

Answer 10

Warfarin is well-known to bind to albumin. The total concentration is 1mg/L:
-Bound: 0.99mg/L.
-Unbound: 0.01mmg/L.
therefore the apparent volume is:
-Total: 10mg/1mg/L = 10L.
-Unbound: 10mg/0.01mg/L = 1000L.
The unbound drug is the only part that is pharmacologically available and that can be metabolised by enzymes and pass across the glomerulus and get eliminated in urine. this is because albumin cannot get across the glomerulus as it is too big.

Question 11

What is total concentration?

Answer 11

The sum of bound concentration(bound to plasma proteins) and the unbound concentration.

Question 12

What typically gets measured in plasma?

Answer 12

Typically the total concentration is measured, even though you should really use unbound concentration. This is due to costs and inconvenience using the unbound concentration. Much cheaper to measure drug concentrations that are bigger.

Question 13

To work out loading dose is it fine to use total concentration?

Answer 13

It is fine to use total concentration, to work out the apparent volume. But as long as you use the total concentration with the apparent total volume distribution of the drug then the loading dose will still be the same as if you used unbound concentration with the apparent unbound volume distribution.

Question 14

What is the concern with displacement of drugs?

Answer 14

Say you are giving a person warfarin, and you give them another drug that can displace warfarin (unbind it form plasma proteins) then the drug (warfarin) will become pharmacologically active. If we displace drug from plasma, we will only be concerned with 1/4 of the amount of drug in the body. Ibuprofen will displace 10% of the 25% of displaceable warfarin can be displaced - so only 2.5% of warfarin in the body can be displaced from plasma proteins once warfarin is combined with ibuprofen. This means that as soon as you give the ibuprofen, it will displace the warfarin, and the unbound concentration will go up by 2.5%. This will have no pharmacological effect/no detectable change. If you increase the concentration by 25% or 50% you may suspect to see a change. Ibuprofen doesn’t change the clearance of warfarin, so clearance is unchanged. Once the extra 2.5% extra of warfarin ahs been metabolized, the concentration will go back to its original value.

Question 15

What is the apparent volume of distribution of warfarin?

Answer 15

10L - less than ECF, greater than blood. Plasma protein binding.

Question 16

What is the apparent volume of distribution of gentamicin?

Answer 16

18L - once in the body it stays in the ECF (doesn’t get into cells). The physical volume is very similar to the apparent volume.

Question 17

What is the apparent volume of distribution of theophylline?

Answer 17

35L - this is the same as total body water. Crosses cell membranes.

Question 18

What is the apparent volume of distribution of digoxin?

Answer 18

500L - this is due to binding to Potassium/Sodium/ATPase. If you have small muscle mass you’ll have a smaller volume of distribution. Relative to their body weight, obese patients, old people and sick people. In terms of using digoxin, the loading dose will need to be smaller with a person who has reduced muscle mass. This is the same thing for someone who has chronic kidney failure - smaller volume of distribution with digoxin.

Question 19

Describe pharmacokinetic compartments?

Answer 19

Think about the time course of distribution.

1. One compartment model: if you put a known amount of water into a beaker, the concentration will increase at a specific time. If there is no a beaker with fluid going in and out (steady state), and you put drug into that system (assuming drug is rapidly mixed) the initial concentration will reflect the amount you’ve put into the beaker. then drug will be eliminated, and as this happens the concentration will fall.
2. Two compartment model: If you add extra volume to the beaker but no elimination form the system, the concentration will initially represent plasma volume (no elimination form the system), concentration falls due to distribution to the tissues (to the second connected beaker). If elimination occurs as well, the initial concentration is due to the drug first being introduced, then there is distribution to the tissues as well as elimination. Elimination occurs all the time, in this model distribution and elimination are occurring parallel.