drug distribution

Question 1

To be active a drug must

Answer 1

leave the blood stream and enter the inter or intracellular spaces.

Question 2

Once a drug has been absorbed it must be available for

Answer 2

biological action and distribution to the tissues.

Question 3

Drug Distribution =

Answer 3

Reversible Transfer of a Drug between the Blood and the Extra Vascular Fluids and Tissues of the body (for example, fat, muscle, and brain tissue).

Question 4

Tissue Distribution takes into account

Answer 4

• Plasma protein binding
• Tissue perfusion
• Membrane characteristics
  - Blood-brain barrier
  - Blood-testes/ovary barrier
  - Lipid soluble drugs
  - Actively transported
• Transport mechanisms
• Diseases and other drugs (esp renal failure, liver disease, obesity)
• Elimination

Question 5

Plasma protein binding:

Only unbound drug is

Answer 5

biologically active.

Question 6

Many drugs bind to proteins in the plasma such as

Answer 6

albumin or a1-glycoprotein (eg phenytoin).

Binding is reversible.

Question 7

Plasma protein binding:

Amount of bound drug can be changed by:

Answer 7

Renal failure
Hypoalbuminaemia (level of albumin in the blood is low.)
Pregnancy
Other drugs (major factor)
Saturability of binding

Question 8

Why does protein binding matter?

Answer 8

For this to be an important factor, the drug must be more than 90% bound and the tissue distribution small.

eg-
If a drug is 96% protein bound then only 4% of the drug is free and available for action.
If the unbound level changes to 6% then plasma levels of free drug will increase by 50%.

Question 9

As many drugs have an ideal therapeutic range over which they are active, it is important to characterise certain parameters such as

Answer 9

• volume of distribution
• clearance
• half-life.

Question 10

The greater the Vd (Apparent Volume Of Distribution) the greater the ability of the drug to

Answer 10

diffuse into and through membranes.

Question 11

In theory the Vd should be

Answer 11

42L.

Question 12

If Vd stays in the extracellular fluid but can not penetrate cells =

Answer 12

12L.

Question 13

If Vd is highly protein bound =

Answer 13

3L (warfarin).

Question 14

Clearance of drug =

Answer 14

theoretical volume from which a drug is completely removed over a period of time.
Measure of elimination.

Question 15

Clearance of drug is dependent on

Answer 15

• Concentration and urine flow rate for renal clearance.

- Metabolism and biliary excretion for hepatic clearance.

Question 16

half life =

Answer 16

Time taken for the drug concentration in the blood to decline to half of the current value.
Half life depends on the volume of distribution and rate of clearance.

Question 17

Prolongation of the half life will increase

Answer 17

increase the toxicity of a drug.

- due to reduction in clearance
- due to a large volume of distribution (amiodarone)

Knowledge of the half life will help us to work out how often a drug needs to be administered.

Question 18

To have a therapeutic benefit most drugs needed to be given

Answer 18

chronically.
Plasma levels of a drug take many doses before they stabilise, usually 4-5 half-lives.
This may necessitate a loading dose.

Question 19

Drug Elimination =

Answer 19

removal of active drug and matabolites from the body.

This determines the length of action of the drug.

Question 20

Drug Elimination is made up of 2 parts:

Answer 20

Drug Metabolism (usually in the liver)
Drug Excretion (usually in the kidney but also biliary system/gut, lung, milk)

Question 21

primary organ for drug excretion

Answer 21

kidneys

Question 22

Excretion

Three principal mechanisms are used:

Answer 22

• Glomerular filtration
• Passive tubular reabsorption
• Active tubular secretion

Renal damage is therefore important in causing drug toxicity.

Question 23

The glomerulus filters

Answer 23

All unbound drugs as long as their molecular size, charge or shape are not excessively large.
(190 litres of fluid a day)

Question 24

Factors that affect the glomerular filtration rate will

Answer 24

reduce the clearance of a drug.

Question 25

Active Tubular Secretion

Answer 25

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 26

Passive Tubular Reabsorption

As the filtrate moves down

Answer 26

renal tubule any drug present is concentrated.

Passive diffusion occurs in the distal tubule and collecting duct.
Only un-ionised drugs such as weak acids are reabsorbed.

Question 27

Passive diffusion along the concentration gradient allows

Answer 27

the drug to move back through the tubule into the circulation.

Can also be affected by renal failure.

Question 28

Biliary Secretion

Answer 28

The liver secretes 1 litre of bile a day.
Drugs may be passively or actively secreted into the bile.
Biliary secretion accounts for 5-95% of drug elimination for many drugs.

Question 29

entero-hepatic circulation is when

Answer 29

Many drugs are reabsorbed from the bile into the circulation.
It continues until the drug is metabolised in the liver or excreted by the kidneys.

Question 30

Metabolism in the liver often leads to

Answer 30

conjugation of the drug.

The conjugated drug is not reabsorbed from the intestine.

Question 31

Damage to the liver may

Answer 31

reduce the rates of conjugation and biliary secretion and so allow the build up or reabsorption of the drug with resultant toxicity.