Drug Distribution

Question 1

What does drug distribution refer to?

Answer 1

the reversible transfer of a drug between the blood and the extra vascular fluids and tissues of the bidy.

Question 2

What is tissue distribution dependent on?

Answer 2

• plasma protein binding
• tissue perfusion
• membrane characteristics
• transport mechanisms
• diseases and other drugs
• elimination

Question 3

What proteins do drugs bind to in the plasma?

Answer 3

• albumin

- a1-glycoprotein

Question 4

What must a drug be to be biologically active?

Answer 4

Unbound

Question 5

How can the amount of bound drug be changed?

Answer 5

• renal failure
• hypoalbuminaemia
• pregnancy
• other drugs
• saturability of binding

Question 6

Why does protein binding matter?

Answer 6

• for this to be an important factor the drug must be more than 90% bound and the tissue distribution small

Question 7

What parameters are important to characterise in therapeutic range?

Answer 7

• volume of distribution
• clearance
• half-life

Question 8

What is the apparent volume of distribution?

Answer 8

The volume in which the amount of drug would be uniformly distributed to produce the observed blood concentration

Question 9

What does a greater Vd tell us?

Answer 9

the greater the ability of the drug to diffuse into and through membranes

Question 10

In theory what should the value of Vd be?

Answer 10

42L

Question 11

If the drug stays in the extracellular fluid but cannot penetrate cells what is the theoretical value of Vd?

Answer 11

12L

Question 12

What is the theoretical value of Vd if the drug is highly protein bound?

Answer 12

3L

Question 13

What is the theoretical value of Vd if the drug is sequestered in extravascular lipid compartment?

Answer 13

> 40L

Question 14

What is clearance?

Answer 14

the theoretical volume of fluid from which a drug is completely removed over a period of time

Question 15

What is clearance a measure of?

Answer 15

elimination

Question 16

What is clearance dependent on?

Answer 16

• concentration and urine flow rate for renal clearance

- metabolism and biliary excretion for hepatic clearance

Question 17

What is half-life?

Answer 17

the time taken for the drug concentration in the blood to decline to half of the current value

Question 18

What is half life dependent on?

Answer 18

the volume of distribution and rate of clearance

Question 19

Why will prolongation of the half life increase the toxicity of the drug?

Answer 19

• due to reduction in clearance

- due to large volume of distribution

Question 20

How must most drugs be given to have a therapeutic benefit?

Answer 20

chronically

Question 21

When is steady state concentration achieved?

Answer 21

approximately after 4 half times

Question 22

What is the relationship between time to steady state concentration and dosage

Answer 22

they are independent

Question 23

What is drug elimination?

Answer 23

the removal of active drug and metabolites from the body

Question 24

What is drug elimination made up of?

Answer 24

-drug metabolism (usually in the liver)
drug excretion (usually in the kidney but also biliary system/gut, lung, milk)

Question 25

What are the primary organs involved in drug excretion?

Answer 25

kidneys

Question 26

What are the 3 principal mechanisms used in excretion?

Answer 26

• glomerular filtration
• passive tubular reabsorption
• active tubular secretin

Question 27

How much is filtered by the glomerulus each day?

Answer 27

190 litres

Question 28

What will be filtered by the glomerulus?

Answer 28

all unbound drugs as long as their molecular size, charge or shape are not excessively large.

Question 29

What will reduce the clearance of a drug?

Answer 29

factors that affect the glomerular filtration

Question 30

Describe active tubular secretion.

Answer 30

• some drugs are actively secreted into the proximal tubule (acidic and basic compounds)
• this is the most important system for eliminating protein bound cationic and anionic drugs.

Question 31

How does passive tubular reabsorption occur?

Answer 31

• as the filtrate moves down the renal tubule any drug present is concentrated.
• passive diffusion along the concentration gradient allows the drug to move back through the tubule into the circulation.

Question 32

Where does passive diffusion occur?

Answer 32

In the distal tubule and collecting duct

Question 33

What drugs can be reabsorbed?

Answer 33

un-ionised drugs such as weak acids

Question 34

How much bile does the liver secrete a day?

Answer 34

1 litre

Question 35

How can drugs be secreted in bile?

Answer 35

actively or passively

Question 36

What is entero-hepatic circulation?

Answer 36

many drugs are then reabsorbed from the bile into the circulation

Question 37

What does metabolism in the liver often leads to?

Answer 37

• conjugation of the drug

- the conjugated drug is not reabsorbed from the intestine

Question 38

What may reduce the rates of conjugation and biliary secretion?

Answer 38

damage to the liver which then allows the build up or reabsorption of the drug with resultant toxicity