Drug Distribution

Question 1

What are the factors which affect drug distribution once they are absorbed into the blood stream?

Answer 1

• Cardiac output and blood flow (e.g. fat does not get much blood flow, so drug will not distribute there very fast)
• Plasma protein binding (drug that is bound to plasma proteins will remain within the plasma)
• Lipid solubility (hydrophobic molecules will pass across membrane more easily)
• Degree of drug ionisation (charged molecules will not readily pass across membrane)
• pH of compartments (most drugs weak acids or bases so their charge will vary on the pH of the compartment)
• Capillary permeability

Question 2

Which factors affecting drug distribution also affected extent of drug absorption ?

Answer 2

• Lipid solubility
• Degree of drug ionisation
• pH of compartments

Question 3

What is the cardiac output to the kidney ? The blood flow to it ?

Answer 3

20% of CO

450 ml/min/100g tissue

Question 4

What is the cardiac output to the liver ? The blood flow to it ?

Answer 4

10% of CO

25 ml/min/100g tissue

Question 5

What is the cardiac output to the heart ? The blood flow to it ?

Answer 5

4% of CO

70 ml/min/100g tissue

Question 6

What is the cardiac output to the brain ? The blood flow to it ?

Answer 6

13% of CO

55 ml/min/100g tissue

Question 7

What is the cardiac output to the skeletal muscles ? The blood flow to it ?

Answer 7

20% of CO

3 ml/min/100g tissue

Question 8

What is the cardiac output to the fat ? The blood flow to it ?

Answer 8

2% of CO

1 ml/min/100g tissue

Question 9

What is the main factor affecting initial rate of distribution of drugs ? Give an example of a tissue which would initially receive low distribution of blood due to this factor.

Answer 9

Blood flow (for hydrophobic drugs) and diffusion characteristics of the drug (for hydrophilic drugs)

Blood flow to fat

Question 10

What is the predominate plasma binding protein ? What is its concentration in blood ?

Answer 10

Albumin

40 g/L

Question 11

How do drugs bind to albumin ?

Answer 11

• Lipid-soluble drugs bind non-specifically (around surface of it)
• Weak acids bind to a specific, saturable site (limited amount of capacity on albumin to bind a weak acid)

Question 12

Give a clinical example as to why binding of drugs to albumin might be significant.

Answer 12

If 2 drugs competing as 2 weak acids, one with greater affinity for albumin will dislodge the other (so higher free concentration of the dislodged drug).
For instance, aspirin will dislodge warfarin from albumin, allowing free warfarin concentration to rise from 1% in the blood in normal conditions, to 2-3%.

Question 13

What are possible reasons for albumin levels in the blood to rise or decrease ? What is the result of each of these on free drug levels.

Answer 13

Hyperalbuminemia: Due to dehydration (decreases free drug levels)

Hypoalbuminemia: Due to burns, renal disease (causing proteinuria), hepatic disease (because liver makes albumin), malnutrition (increases free drug levels)

Question 14

What are some factors which affect the degree of binding of drugs with albumin ?

Answer 14

• Temperature
• pH
• Drug interactions

Question 15

Why is it a problem to lose albumin (separate from drug-binding issues) ?

Answer 15

Because albumin contributes to oncotic pressure

Question 16

List the main types of capillaries and where each if found.

Answer 16

1. Continuous Capillaries: very little gaps between cells, quite a few junctions so not a huge amount of cells or proteins traveling across membrane (Most tissues)
2. Fenestrated Capillaries: Smaller molecules can make it across holes in membrane (Skeletal muscle)
3. Sinusoid/Discontinuous Capillaries: larger molecules can make it across membrane (Liver)

Question 17

Which type of molecule will go through continuous capillaries ? through fenestrated capillaries ? through discontinuous capillaries ?

Answer 17

Continuous capillaries: lipophobic molecules (gases diffuse the fastest, followed by small molecules, followed by large molecules)
Fenestrated capillaries: small lipophobic molecules
Sinusoid capillaries: RBCs, large lipophobic molecules

Question 18

Give an example of a location in the brain with continuous capillaries.

Answer 18

BBB

Question 19

Describe how transport occurs across the BBB.

Answer 19

Very tight junctions between endothelial cells + basal membrane + astrocytic foot processes all serve to insulate the CNS (to prevent large molecules etc. getting through)

Hence, drugs need to be lipophilic to get across BBB (if so then they will have widespread effects because they’ll be able to get in all kinds of tissues) OR get transported actively

Question 20

What is the function of the BBB ?

Answer 20

Physical and functional barrier

Question 21

Identify a factor which can change the ability of drugs to pass through the BBB.

Answer 21

Disease state

For instance, meningitis disrupts BBB and allows more permeability

Question 22

Identify possible issues associated with specific specialised barriers / compartments (especially with regards to drug distribution to those compartments).

Answer 22

1) Placenta
Tight endothelial cell junctions in maternal and fetal capillaries
Partially protective, except with:
– lipid soluble drugs (must avoid some antihypertensive drugs)
– unionised forms of weak acids and bases
(If drug gets to fetal circulation, can get ion trapping in certain tissues if the pH in said tissues is different, resulting in gradual accumulation of drugs)

2) Chronic abscesses
- Avascular tissue compartments, so difficult to get antibiotics to abscess (no blood flow, so rate of drug distribution will be slow)
- Generally unfavorable pH to get distribution

3) Lung infection
-Local low PO2 and high PCO2 cause vasoconstriction (if a chest infection occurs, and an aspect of that lung is not being perfused optimally, a less than ideal amount
of blood flow will go to it so rate of drug distribution will be slow)

Question 23

Identify the fluid volume present in each of the main fluid substances of the body.

Answer 23

Extracellular fluid= 15 L

• Plasma = 3 L
• Interstitial fluids = 12 L

Intracellular fluid = 27 L

Total body water (for a 70kg adult) = 42 L

Question 24

Which kinds of molecules distribute specifically in each of the fluid substances of the body ?

Answer 24

Extracellular fluid-
Large, water-soluble molecules (e.g. mannitol)

Plasma-
Highly plasma-bound molecules
Highly charged molecules
Very large molecules (e.g. heparin)

All of the fluid substances (distribute around all body water without discriminating)-
Small, water-soluble molecules (e.g. ethanol)

Question 25

Name three reservoirs of the body (not fluid compartments). Name drugs which stick to these reservoirs.

Answer 25

Fat (Marijuana) Bone (Alendronate) Teeth

Question 26

Explain how volume of distribution works.

Answer 26

If we take a bucket, that is 10 L in capacity. We put a membrane within that (permable to drugs with the right properties). A) If drug distributes readily with no barriers, case of working out how much drug is diluted by (e.g. ethanol, distributes readily, explained by 42 L) B) Protein in central compartment which binds that drug and keeps it inside compartment, only little bit of drug will pass through membrane, but majority will stay in central compartment (compartmentalisation occurring so drug explained by 3L instead of 42L) C) Binding protein is outside of central compartment so still have bucket of the same size and the membrane is still permeable but now something binding to it in external compartment (e.g. bone for biphosphonates)/ The drug can readily diffuse across membrane but then gets stuck outside (so when sample from middle, get low concentration because drug has been distributed from central compartment. Can be explained by a) hundreds/thousands of liters or b) a reservoir effect) (usually/always b, which means Vd is not always physiologically possible!)

Question 27

Define apparent volume of distribution (Vd).

Answer 27

The theoretical volume required to account for the amount of drug in the body

Question 28

How do you calculate the apparent volume of distribution (Vd) of a drug ? What are the units of Vd ?

Answer 28

total amount of drug in the body / blood plasma concentration of drug Units are in litres (L) or sometimes L/kg of body weight.

Question 29

When given a Vd, how can you figure out which drug is most likely used ?

Answer 29

Multiply the Vd value by the weight of said person to obtain a volume in L. This volume should be more or less the volume in a specific fluid compartment (or all fluid compartments together). Specific types of molecules tend to stick to specific fluid compartments so this can help you figure out that drug used.

Question 30

What could the following drug be ? | Drug A = Vd of 0.2 L/kg

Answer 30

0.2L/kg x 70kg (assuming average physiological weight) = 14L This means the drug is likely distributing in extracellular fluid. Could be mannitol

Question 31

What could the following drug be ? | Drug B = Vd of 0.6 L/kg

Answer 31

0.6L/kg x 70kg = 42L This means the drug will likely distribute throughout the body water without discriminating. Could be ethanol

Question 32

What could the following drug be ? | Drug C = Vd of 6.0 L/kg

Answer 32

6.0L/kg x 70kg = 420 L This means there is likely a reservoir effect going on. Could be alendronate.

Question 33

Distinguish between the single compartment and the two compartment model of distribution.

Answer 33

1) Single compartment model of distribution - IV drugs start out circulating in a single, well-stirred compartment (PLASMA + potentially EXTRACELLULAR FLUID, depending on whether drug travels there or just stays in plasma, like warfarin). As soon as drug is in this compartment, it is susceptible to excretion and metabolism. - This first compartment can be explained as one volume (Vd) This model assumes rapid mixing of drug in plasma, and assumes drug in plasma is in rapid equilibrium with drug in extravascular tissues. 2) Two compartment model of distribution - IV drugs start out circulating in a central compartment (e.g. blood and well-perfused tissues). - Some drugs will be excreted/metabolised, whilst others will move on to a second compartment (peripheral compartment, i.e. poorly perfused tissues) for instance biphosphonates in bone. Only way for them to get out again is for them to get back into the central compartment where they are susceptible to excretion and metabolism

Question 34

Explain the clinical relevance of Vd.

Answer 34

Vd can be used to determine a loading dose to achieve a desired plasma concentration of drug. Key to understand how you can give peak plasma concentration with a single bolus dose (if concerned only about getting to peak plasma concentration, not to steady state plasma concentration. In that case, clearance information is unnecessary)

Question 35

What are factors in a person which affect Vd?

Answer 35

``` Vd varies with: – Height – Weight – Age – Fluid accumulation • ascites • oedema • pleural effusion – Accumulation of fat – Permeability of capillaries (to things which would normally stay in plasma) ```

Question 36

Distinguish between Vd and CL, in terms of the information they provide.

Answer 36

- Vd tells you information about peak plasma concentration (single doses) - Clearance gives you information about steady state plasma concentration - Both together, give you the half life of a drug