S3: Drug Distribution

Question 1

What is drug distribution?

Answer 1

it is the distribution of drugs after its been absorbed.

Question 2

Why do we aim to get drugs into the circulation?

Answer 2

It is the circulation that will deliver to drug to its site of action. The drug doesn’t often stay in the circulation and gets sequestered into surrounding tissues, this is the dispersion process of the drug after its been absorbed which means there will be lower concentration of the drug around the body.

Question 3

Why do we adjust the dosage of drugs?

Answer 3

• Adjusting the dosage of drugs allows us to control the concentration of drug going around our body.
• It is important for drugs that have a very narrow therapeutic window, we need to know where and how the drug is being distributed in the body.

Question 4

Describe the route of a drug from i.v. bolus dose

Answer 4

• No absorption so drug gets into the blood vessels straight away.
• However drug does not stay in the blood stream.
• Diffusion can take place especially for lipophilic drugs and they can diffuse out of blood vessels (intravascular space) into another compartment (extravascular space e,g, interstitium or tissues) outside of the blood vessels.
• Once the drug gets into the tissue (esp. lipophilic drugs into adipose tissue) they may stay there for quite a while and this links to the point of clearance.
  That if these tissues are poorly perfused, which adipose tissue is, then it will impact on the clearance as the drug will be slowly removed.

Question 5

Why do we use the drug concentration in the blood to estimate the distribution of the drug?

Answer 5

As the drug is distributed so much it is difficult to calculate the volume the drug is dissolved in. For convenience, we use the drug concentration in the blood (whole, plasma or serum) to estimate the relative distribution of the drug (to gauge how much stays in the blood or goes to tissues etc).

• In general, the higher the concentration in the blood, the higher the concentration at the site of action.
• Plasma concentration is more reliable than ISF.

Question 6

Describe the graph of plasma concentration against time

Answer 6

• The drug inside the blood vessel will be delivered more quickly to the well perfused areas of the body e.g. brain, liver, lungs, (highly vascularized areas).
• With a variable delay, the drug will start getting into the poorly perfused areas of the body, this depends on the individual blood flow to areas of the body.
• As we can see the concentration of the drug in the plasma decreases as the drug moves to the well-perfused areas and poorly-perfused areas. This is as the drug is distributed out of the plasma into surrounding compartments.
• We must also remember that while the drug is being taken up by tissues it is also being metabolised in these tissues and being excreted. For example in the liver, being metabolised to a more water soluble drug so it can be removed by the kidney.

Question 7

What are the two factors affecting the plasma drug concentration?

Answer 7

• The drug distribution

- The elimination process of the body of the drug

Question 8

Describe first order kinetics of drugs

Answer 8

• Lots of enzymes available and ready to work.
• Most drugs follow this mechanism so it makes drugs more predictable.
• The rate of metabolism is proportional to drug concentration.
• A constant fraction of the drug is removed as we increase dose. So an increase in the amount going in means there is an increase in the amount going out. Levels of drug are therefore not building up in our body and there are no saturation points.
• First order kinetics also means the drug has a constant half life (the amount of time for your body to decrease the drug concentration by half). This makes its kinetics more predictable as the time taken for body to remove a drug can be estimated after a blood test.

Question 9

Why is knowing about first order kinetics important in designing dosage regimens?

Answer 9

As long as nothing is saturated and they follow the first order drug kinetics, the properties of drug distribution and elimination is the same for whatever dose of the drug. It is therefore more predictable and this is used when deciding on dosage.

Question 10

Describe zero order kinetics of drugs

Answer 10

• Maximum capacity is occurring and something is saturated e.g. enzyme, transporter.
• This is rarer in drugs and usually occurs when patient overdoses.
• It is unpredictable and dangerous with drugs with a small therapeutic window.
• Drugs such as alcohol are more likely to saturate enzymes. Therapeutically phenytoin can also follow zero-order kinetics.
• In zero order kinetics, all out enzymes are working on our substrate (the drug concentration) so an increase in plasma concentration does not increase drug metabolism. The rate of metabolism becomes independent of drug concentration.
• A constant amount of drug is being removed per unit time which therefore promotes accumulation of the drug in the system as the body is unable to increase its capacity to remove the drug which the [drug] increases. The bigger the dose, the longer it will take for the body to remove it.
• However, remember that any drug that is at zero order kinetics will not remain at that forever as the body slowly removes the drug and it will bring it down below the saturation point and start handling it will first order kinetics.

Question 11

Why do we tend to avoid zero order kinetics with drug design?

Answer 11

The kinetics are more unpredictable so it is dangerous with drugs with a small therapeutic window. We only use drugs that follow zero order kinetics if there is a good monitoring system in place looking at the metabolites formed and their toxic effects. These drugs will need to be used in a carefully controlled manner.

Question 12

What are the four parameters used to design dosing regimens?

Answer 12

1. (Apparent) volume of distribution
2. Clearance
3. Bioavailability
4. First/Zero order kinetics

Question 13

How do we calculate the volume of drug distribution (include eq)?

Answer 13

We use the concentration of drug in the plasma to calculate the apparent distribution. The concept of drug distribution is the amount of drug inside the blood vessels in comparison to outside the blood circulation.

• Total amount of drug / [Plasma] = Apparent volume of distribution (Vd).
• e.g. 20 mg i.v. / 2mg/L = 10 L. If a person has 4 L of blood it means 6 L would be in the extravascular space such as tissues.
• Despite being a virtual/apparent amount, this equation is used as it tells us the extent to which the drug has been distributed out of the blood, a distribution larger than 4-6L means that some of the drug has moved out of the blood circulation. We aren’t able to tell where it has gone, just the relative amount that has left the blood.
• The greater the apparent volume of distribution, the more widely the drug has been dispersed out of the blood.

Question 14

What affects how a drug is dispersed?

Answer 14

It is influenced by the chemical structure of the drug and hence the lipid/water solubility of the drug.

• For a drug that binds heavily to the plasma proteins, it is unlikely to have high volume distribution because they are tied to the protein in the blood essentially trapping the drug.
• For more lipid soluble drugs, these are more likely to diffuse out of the blood through the barriers and be widely dispersed therefore having higher Vd.

Question 15

Why does volume distribution affect dosage?

Answer 15

If the drug is widely dispersed, it means that there will be a lower concentration in the blood. The dose therefore has to be adjusted in order to receive the concentration that is optimal in the blood.

Question 16

How is drug clearance calculated (include eq)?

Answer 16

Clearance tells us how quickly a drug is being eliminated but not the mechanism it occurs by. It is a parameter used to measure the elimination of the drug. Plasma clearance (Cl) is the volume of plasma cleared of the drug per unit time (ml min-1).

• Clearance = Rate of elimination/[Drug plasma]
• For first order kinetics the clearance is constant.

Question 17

Why is estimating the time course of the [drug] in circulation with i.v. drug doses (e.g. Vd, Cl) not realistic?

Answer 17

• Most medicines are not given i.v. but orally.
• Most medicines are given as multiple doses rather than one (thinks links to steady state principle).
• Kinetics can actually be altered by age and diseases e.g. liver enzymes, kidney function.

Question 18

Describe bioavailability of a drug

Answer 18

Bioavailability (F) is the fraction of drug in circulation compared to dose. It measures the extent of absorption so for i.v. drugs, they have F=1. other routes of administration will usually have F < 1.

Question 19

How is bioavailability of a drug measured (with eq)?

Answer 19

• Give equal oral and i.v. doses of drug and plot the concentration of drug in plasma over time.
• Measure area under both curves (AUC) or i.v. and oral.
• AUC oral/ AUC i.v. = F

Question 20

What is low bioavailability caused by?

Answer 20

• Poor
• Chemical reactions at at site of delivery (drug is metabolised at site so less remains in the blood).
• First-pass metabolism, mainly liver - if a drug is given orally, drug is shunted to liver before being released to rest of the circulation. However, sometimes the drug is metabolised during its first round of the circulation e.g. By enzymes in the liver.
  If bioavailability is low, may have to change structure of drug etc.

Question 21

What is choice of administration of drug guided by?

Answer 21

• Bioavailability
• Chemical properties of the drug
• Convenience
• Need to control specificity of action
• Desired onset/duration/offset of action (how long will stay at desired conc. range etc.)

Question 22

Difference between rate of absorption and bioavailability

Answer 22

There is a difference between rate of absorption and bioavailability.
The time it takes to reach maximum conc. is dependent on the rate of absorption, which is how quickly the drug is being absorbed into the body.
A drug may be absorbed slowly but still most of it is absorbed into the body (high extent of bioavailability).

Question 23

What is a ‘steady state’ of drug concentration?

Answer 23

Steady state can be said to be where on average the rate of input of drug is equal to the rate of elimination, there is an equilibrium. Dosage rate = rate of elimination.

Question 24

How is steady state of drug achieved?

Answer 24

• This occurs mostly with multiple dosing which is a controlled way of accumulating the drug in our circulation.
• We need to give the dosages in intervals so that we build up the concentration and we need to give these additional doses before [drug] falls to zero.
• It is a compromise between giving large dose infrequently and small dose more frequently to reach steady state and minimise drug level fluctuation.. We need to consider compliance of patient, safety of drugs as some are toxic at higher levels.

Question 25

What affects how much the drug varies at steady state?

Answer 25

• The drugs halflife.
• The dosage interval.
  Broadly speaking, the shorter the half life there needs to be a shorter time interval as the drug decays faster.

Question 26

Dosing rate equations (to achieve steady state)

Answer 26

• Dosing rate (input) = Rate of elimination (output) at steady state
• Dosing rate = Clearance x Css where Css is the steady state concentration
• Dosing rate x F = Clearance x Css

Question 27

Describe how steady state is reached in terms of half life, loading dose and maintenance dose

Answer 27

epeated doses of a drug eventually produce a steady state (plateau) concentration of a drug.
The time taken to reach steady state for any drug is 4-5 half lives, when the dosage is changed e.g. increased a new (higher) steady state will be reached in 4-5 half lives.
Therefore if a half-life is a few days it will take a long while.

If you can’t wait for drugs with long half-lives to reach steady state you can accelerate this by give a loading dose (large initial dose to reach desirable level and then use smaller doses to keep it there) and then a smaller maintenance dose to maintain that level in the long run.