Drug Absorption and Distribution

Question 1

What does ADME stand for?

Answer 1

Absorption, Distribution, Metabolism and Elimination/Excretion

Question 2

What is drug absorption?

Answer 2

Absorption from the site of administration to entry into the plasma

Question 3

What is drug distribution?

Answer 3

Drug reversibly leaves the bloodstream and is distributed into the interstitial and intracellular fluids

Question 4

What is drug metabolism?

Answer 4

Drug transformation by the liver and other tissues

Question 5

What is drug excretion?

Answer 5

Drug and/or drug metabolites exerted in urine, faeces or bile

Question 6

What 4 ways do drugs move around the body?

Answer 6

Bulk flow (via circulatory system), diffusion over short distances, solubility and size of molecules.

Question 7

What are the barriers between compartments of the body?

Answer 7

Cell membranes (separates extracellular from intracellular)

Question 8

What are the 4 ways small molecules can cross cell membranes?

Answer 8

Passive/facilitated diffusion, active transport and endocytosis/pinocytosis

Question 9

What is passive diffusion?

Answer 9

Directly through the lipid or through aqueous pores formed by aquaporins that transverse the lipid bilayer. (how many lipid soluble drugs cross the cell membrane)

Question 10

What is facilitated diffusion?

Answer 10

Via a specialised carrier protein that binds to the drug on one side of the bind molecule on one side of the membrane, which changes the conformation of the bind molecule and drug is released on the other side. No energy required but a concentration gradient is

Question 11

What is active transport?

Answer 11

Via specialised carrier proteins that change conformation when ATP binds hence why it needs energy (active). Used to move drugs against the concentration gradient

Question 12

What is endocytosis?

Answer 12

A part of the membrane is invaginated by a small vesicle that encases the drug (which is then released inside the cell) - also called pinocytosis

Question 13

What is saturation kinetics and when is it shown?

Answer 13

There is a limited amount of the drug transporter which can often lead to a build up of drugs waiting to be transported - shown in facilitated diffusion and active transport

Question 14

What are the principal sites of carrier mediated drug transport (FD and AT)?

Answer 14

Blood brain barrier, GI tract, placenta, renal tube and biliary tract

Question 15

What drugs is carrier-mediated transport important for?

Answer 15

Ones that are chemically related to endogenous transmitters eg neurotransmitters

Question 16

What is endocytosis important for?

Answer 16

Transport of large drugs across the cell membrane eg Vitamin B12

Question 17

What does the proportion of ionisation in a drug depend on?

Answer 17

pKa and pH as pKa = pH at which the drug is 50% ionised and 50% unionised

Question 18

What form of drugs can often permeate the membrane?

Answer 18

Non-ionised form

Question 19

What types of acids and bases are most drugs?

Answer 19

Weak (don’t fully dissociate)

Question 20

What are the Henderson-Hasselbalch equations for determination of ionisations of acids and bases

Answer 20

10^(pKa-pH) = (BH+/B)
10^(pKa-pH) = (AH/A-)

Question 21

Do weak bases prefer low or high pH? Why?

Answer 21

Low due to facilitation of absorption

Question 22

Do weak acids prefer low or high pH? Why?

Answer 22

High due to facilitation of absorption

Question 23

In what compartments are small water-soluble molecules found?

Answer 23

Total body water

Question 24

In what compartments are large-water soluble molecules found?

Answer 24

Extracellular compartments

Question 25

What types of molecules are found in blood plasma?

Answer 25

High plasma protein-bound molecules, large molecules and highly charged molecules

Question 26

In what compartments are highly lipid soluble molecules found?

Answer 26

Adipose tissue

Question 27

What types of molecules are found in bone and teeth?

Answer 27

Certain ions

Question 28

What is the Apparent Volume of Distribution?

Answer 28

The extent to which a drug partitions between the plasma and tissue compartments
Vd = dose/[drug]plasma

Question 29

What is [drug]plasma?

Answer 29

Amount added/ volume of beaker

Question 30

Is Vd an actual volume?

Answer 30

No - many drugs will have a Vd greater than the body’s total water volume (41L). Volume is metaphorical

Question 31

How do physiochemical properties affect Vd?

Answer 31

It is more difficult for hydrophilic/ionised drugs to cross the membrane and so Vd is close to 41L, however it is easier for lipophilic drugs and so Vd is usually > total body volume

Question 32

How do vascular and non-vascular compartments affect Vd?

Answer 32

Vascular (eg blood) decreases Vd and non-vascular (eg tissue) increases Vd

Question 33

What will require a higher dose, a drug with a high Vd or one with low Vd? (both equal potency)

Answer 33

High Vd

Question 34

What is the most abundant plasma protein?

Answer 34

Albumin

Question 35

What is the binding like between drugs and albumin?

Answer 35

Low affinity binds via electrostatic and hydrophobic forces

Question 36

What does plasma protein binding do?

Answer 36

Reduces the availability of the drug for diffusion to the drug target organ (may also reduces the transport of the drug to non-vascular compartments)

Question 37

How do plasma protein binding affect Vd?

Answer 37

No plasma protein binding = high Vd. Plasma protein binding = low Vd (because plasma protein binding increases the concentration of drug in the plasma)