PK: Drug Distribution

Question 1

Total body water = _______ % of body weight

Answer 1

50-70%

Question 2

Fat = ______ % of body weight

Answer 2

20%

Question 3

EC fluid consists of:

Answer 3

Blood plasma - 4.5%

IS fluid - 16%

Lymph - 1.2%

Question 4

How much of total body water does IC fluid constitute

Answer 4

30-40%

Question 5

What is IC fluid

Answer 5

Sum of all fluid contents of all cells in the body

Question 6

How much of total body water does transcellular fluid constitute

Answer 6

2.5%

Question 7

What is transcellular fluid made up of

Answer 7

CSF

Intraocular fluids

Peritoneal fluids

Pleural fluids

Synovial fluids

Question 8

Body fluid compartments overview

Answer 8

Question 9

Define drug distribution

Answer 9

Process by which a drug reversibly leaves bloodstream and enters the EC fluid and/or cells of the tissue (IC fluid)

Question 10

What are the 3 factors drug distribution depends on

Answer 10

BLOOD FLOW:

• capillary permeability
• capillary structure - BBB due to endothelial cell tight junctions, reduced pores and layers of astrocytes

DRUG STRUCTURE:

• hydrophobic drugs (no net charge) readily move across most membranes
• hydrophilic drugs (charged) do not penetrate cell membranes

BINDING OF DRUGS TO PROTEINS

Question 11

Drug distribution after IV injection

Answer 11

Rapid equilibriation with WELL PERFUSED TISSUES

• Lung
• Kidneys
• Liver
• Heart
• Brain (BBB)
• Intestines

Slower entry to poorly perfused tissues

• Skin
• Skeletal muscle
• Connective Tissue
• Fat

Question 13

Define volume of distribution

Answer 13

The extent of distribution of a drug from plasma to the tissue determines:

• The relationship between plasma conc and total amount of drug in the body
• The amt of drug that has to be administered in order to produce a particular plasma conc

Question 14

Clinical example of Vd

Answer 14

Question 15

Where are drugs with low Vd primarily retained

Answer 15

Within the vascular compartment

Question 16

Where are drugs with high Vd retained

What is the Vd often higher than

Answer 16

Highly distributed into muscle, adipose tissue and other non-vascular compartments

Much higher than the total body water (= 42L)

Question 17

What does the capacity to take up and retain drug depend on

Answer 17

The volume (mass) of the tissue and the density of specific and non-specific binding sites for the drug within that tissue

Question 18

Use of Vd

Answer 18

Vd is the determinant of the loading dose

allows us to get to steady state quicker

If we start with a maintenance dose, it takes some time to accumulate a steady state

Question 19

Formula for loading dose

Effect of High vs low Vd on loading dose

Answer 19

Vd x desired plasma conc

Large Vd - need larger dose to load

Low Vd - need smaller dose to load

Question 20

When might Vd exceed total body volume

Answer 20

For drugs that accumulate outside the plasma compartment (eg in fat or by being bound to tissues)

Question 21

Name 2 drugs localised mainly in plasma (with little in tissues)

Answer 21

Aspirin

Amoxycillin

Question 22

Name 2 drugs that have a similar concentration in both plasma and tissues

Answer 22

Theophylline

Diazepam

Question 23

Name 2 drugs mainly located in tissue, with very little in plasma

Answer 23

Digoxin

Haloperidol

Question 24

Vd of aspirin

Answer 24

9.8

Question 25

Vd of amoxycillin

Answer 25

14

Question 26

Vd of theophylline

Answer 26

35

Question 27

Vd of diazepam

Answer 27

105

Question 28

Vd of digoxin

Answer 28

490

Question 29

Vd of haloperidol

Answer 29

1750

Question 30

Permeability of the BBB

Answer 30

Inflammation can allow normally impermeant substances to enter the brain e.g. penicillin and meningitis In some places, the barrier is leaky e.g. the chemoreceptor trigger zone - domperidone will act here

Question 31

What sort of association is the binding of drugs to plasma proteina

Answer 31

REVERSIBLE association

Question 32

Vd and location of highly protein bound drugs

Answer 32

Highly protein bound drugs tend to remain within the vasculature and thus have low Vd

Question 33

What drugs can cross the capillary membrane

Answer 33

Only free drug

Question 34

State of protein bound drugs

Answer 34

Protein bound drugs are PHARMACOLOGICALLY INACTIVE =\> protein binding slows the rate at which the drug reaches its site of action hence protein bound drug can act as a drug reservoir - as conc of free drug decreases to elimination, the bound drug dissociates from the protein Extensive protein binding will increase the amount of drug that must be absorbed before effective therapeutic levels of unbound drug occur

Question 35

What are the main plasma proteins drugs bind to

Answer 35

Albumin - mainly acidic drugs Beta-globulin & alpha 1 acid glycoprotein - basic drugs

Question 36

What does the amount of drug bound depend on

Answer 36

Conc of free drug Affinity for binding sites Conc of protein

Question 37

Conc of albumin in plasma

Answer 37

0.6 mmol/L 4 g/100ml = 4 g/dL

Question 38

How many binding sites does each albumin molecule have

Answer 38

2 binding sites

Question 39

Drug binding capacity of albumin

Answer 39

1.2 mmol/L Usual therapeutic dose is much less than this - not saturated - fraction bound is independent of drug conc

Question 40

What drugs work at conc near saturation

Answer 40

eg tolbutamide Sulfonamides adding more drug results in a disproportionate increase in free conc

Question 41

In clinical practice, what is the effect of co-administering 2 highly protein bound drugs

Answer 41

Theoretically, it should lead to increased free drug conc - but this does not seem to be a problem in clinical practice

Question 42

4 instances of altered protein binding

Answer 42

REDUCED PROTEIN * hypoalbuminaemia eg low albumin in nephrotic syndrome or hepatic failure URAEMIA * Excess urea in the blood from kidney damage, affects the binding sites such that drugs are less extensively bound than in non-uraemic patients AGE * Lower binding capacity in the foetus and neonates DISPLACEMENT FROM BINDING SITES - COMPETITION * Drug removed from its binding site as a result of competition with another compound eg warfarin

Question 43

Competition example

Answer 43

Question 44

MCQ

Answer 44

Question 45

MCQ

Answer 45