Absorption Lectures

Question 1

Define pharmacodynamics:

Answer 1

What the drug does to the body (receptor binding etc.).

Question 2

Define pharmacokinetics:

Answer 2

What the body does to the drug (LADME).

Question 3

What does LADME stand for? Explain each of the steps

Answer 3

Liberation - Release of the drug from the delivery form
Absorption - Movement of the drug into the blood/plasma (often across a membrane)
Distribution - Movement of the drug into the tissue from the plasma (until equilibrated)
Metabolism - Reaction of the drug into metabolites (for elimination or as pro-drugs)
Elimination - Removal of the drug from the body (typically by metabolism or excretion)

Question 4

In what ways do the release and membrane transport of lipophilic and hydrophilic drugs differ? Explain why.

Answer 4

Lipohilic: Releases slowly (poorly soluble in water), permeates quickly (highly permeable to lipid membrane)

Hydrophilic: Releases quickly (good water solubility), permeates slowly (poorly permeable to lipids).

Question 5

Which stage of absorption would typically dictate the rate of absorption for a lipophilic drug? Why?

Answer 5

The release of the drug since it is the slow step for lipophilic drugs.

Question 6

Which stage of absorption would typically dictate the rate of absorption for a hydrophilic drug? Why?

Answer 6

The permeation of the drug across the lipid bilayer since it is the slow step for hydrophilic drugs.

Question 7

Explain why lipophilic drugs release poorly during absorption:

Answer 7

Lipophilic drugs are hydrophobic and poorly dissolve. They also have a tendency to be retained in tissues.

Question 8

What two steps are involved in dissolution? Elaborate:

Answer 8

1. Surface solvation: Drug on crystal surface dissolves into surrounding solution until stagnant
2. Surface diffusion: Drug diffuses across stagnant layer, into bulk solution

Question 9

Summarise the overall dissolution process:

Answer 9

• Drug located at the crystal surface dissolves to form a stagnant saturated solution layer
• Dissolved drug molecules diffuse across the stagnant layer, into the bulk solution

Question 10

Under what conditions can the Noyes-Whitney equation be used to calculate the rate of dissolution?

Answer 10

Under constant temperature.

Question 11

What are the two membrane transport pathways? Which is major and which is minor?Describe both:

Answer 11

Transcellular (major): Dissolved drug molecules are transported across the membrane via membrane transporters.

Paracellular (minor): Dissolved drug molecules are transported between adjacent cells via cell-cell junctions.

Question 12

Describe the 4 forms of transcellular absorption. Which one is the most common for drugs?

Answer 12

Passive diffusion (most common) - Partition in and out of the lipid bilayer.

Aqueous pore - Hydrophilic channels formed from aquaporin proteins.

Facilitated diffusion - Selective carrier-mediated transport (with gradient).

Active transport - Selective carrier-mediated transport (with/against gradient).

Question 13

What type of molecules best suit passive diffusion? What type of molecules best suit transport via aqueous pores? Why?

Answer 13

Lipophilic molecules are best suited for passive diffusion since it requires partitioning in and out of a lipid membrane.

Hydrophilic molecules are best suited for aqueous pore transport since the channels are hydrophilic in nature and support the passage of small neutral solutes.

Question 14

What is flux? What process is this a part of?

Answer 14

The net movement of molecules. It plays a role in passive diffusion.

Question 15

What is the partition coefficient?

Answer 15

A measure of the dissolution capabilities of a molecule in aqueous and membrane phases.

Question 16

What does logP measure?

Answer 16

The lipophilicity of a (drug) molecule.

Question 17

What does it mean if a drug has a P value of 10? What if the value was 0.2?

Answer 17

It is 10 times more lipid-soluble than water-soluble. If the value is 0.2 then it is 5 times more water-soluble than lipid-soluble.

Question 18

Most drugs are weak acids/bases and can therefore be ionised/unionised.

Explain how this can influence the lipophilicity of a drug.

Answer 18

Drugs are more lipophilic when they are unionised. By residing in a pH that corresponds to that of the drug, they are more unionised and therefore more lipophilic.

Question 19

State the pH partition hypothesis:

Answer 19

Drug accumulates on the side of the membrane where pH favours ionisation.

Question 20

State the pH partition hypothesis:

Answer 20

Drug accumulates on the side of the membrane where pH favours ionisation.

Question 21

Why are the applications of the pH partition hypothesis limited?

Answer 21

It doesn’t account for every variable of lipophilicity and as such can’t be applied in every situation.

Question 22

State Lipinski’s Rule of Five. What is a H bond donor/acceptor?

Answer 22

1. Molecular weight ≤500
2. logP ≤5
3. No more than 5 H bond donors
4. No more than 10 H bond acceptors
5. All of the above rules are in multiples of five

Donor: The one with an O-H bond involved

Acceptor: The one with an O lone pair involved

Question 23

Which one is the H bond donor?

Answer 23

The one with an O-H/F-H/N-H covalent bond involved.

Question 24

Which one is the H bond acceptor?

Answer 24

The one with an O/F/N lone pair involved.

Question 25

What is the therapeutic window?

Answer 25

The rate in drug effect where the results are significant and positive.

Question 26

What happens if the drug concentration/effect is above the therapeutic window?

Answer 26

The effect becomes toxic.

Question 27

What happens if the drug concentration/effect is below the therapeutic window?

Answer 27

The effect is insignificant.

Question 28

What features of the stomach can influence drug absorption?

Answer 28

- Acidity can break down some drugs - Pepsin enzymes break down polypeptide-based drugs

Question 29

Where are most orally administered drugs principally absorbed?

Answer 29

The small intestine, particularly in the jejunum.

Question 30

Explain how meal volume influences gastric emptying and could therefore influence drug absorption.

Answer 30

Larger meals have quicker initial emptying rates; This would cause the drug to be initially exposed to the stomach for less time. Due to decreased gastric exposure, less of the drug may degrade in the stomach and more of it could be absorbed in the SI.

Question 31

State some of the main factors influencing gastric emptying rate:

Answer 31

- Meal volume - State of contents (solutions/suspensions or solids) - Acidity of food - Disease (ulcers)

Question 32

Explain why the house-keeper wave is essential to the gastric passage of certain drugs:

Answer 32

- Some drugs degrade in low pH/pepsin - Require gastro-resistant dosage forms - This prevents regular passage through the pylorus due to size - Housekeeper wave required to carry the DF past the pylorus, into the SI

Question 33

Explain why the house-keeper wave is NOT essential to the gastric passage of certain drugs:

Answer 33

- Some drugs don't degrade in low pH/pepsin - They don't need a gastro-resistant dosage form - Thus, they dissolve in the stomach - As a solute, the drug then leaves the stomach via the pylorus

Question 34

State the four BCS classes:

Answer 34

Class 1 - Highly soluble and permeable Class 2 - Poorly soluble, highly permeable Class 3 - Highly soluble, poorly permeable Class 4 - Poorly soluble and permeable

Question 35

What does BCS stand for? What is its purpose?

Answer 35

Biopharmaceutical classification scheme. To classify pharmaceuticals on their solubility and permeability.

Question 36

State the features of BCS class 1:

Answer 36

Highly soluble and permeable

Question 37

State the features of BCS class 2:

Answer 37

Poorly soluble and highly permeable.

Question 38

State the features of BCS class 3:

Answer 38

Highly soluble and poorly permeable.

Question 39

State the features of BCS class 4:

Answer 39

Poorly soluble and permeable.

Question 40

What is a good rule you can use to remember the BCS classes?

Answer 40

Permeability comes before solubility!!

Question 41

How can the membrane permeability of a drug be improved?

Answer 41

Its structure can be modified by adding lipophilic groups to the drug.

Question 42

What is a prodrug?

Answer 42

A modified version of a drug that has added groups to aid its absorption.

Question 43

Describe the action of most prodrugs:

Answer 43

- Drug has functional groups added to improve absorption - Once absorbed, functional groups are removed by metabolic reactions

Question 44

Do all prodrugs aim to increase lipophilicity? Elaborate.

Answer 44

No. Prodrugs can also be designed to improve hydrophilicity or enzyme recognition as examples.

Question 45

What is the first pass effect? Does it affect all drugs? Why?

Answer 45

The metabolism of drugs on their "first pass" through the liver. No. Some drugs aren't complementary to the liver's metabolic enzymes and thus aren't metabolised.

Question 46

Summarise the events leading up to and including the first pass effect of an oral drug:

Answer 46

- Drug is absorbed in the small intestine - Transported to the liver via the portal vein - As it passes through the liver the drug is considerably metabolised by the liver - Forming active/inactive metabolites

Question 47

How would the first-pass effect influence bioavailability if the metabolite was inactive?

Answer 47

It would decrease the bioavailability of the drug.

Question 48

How would the first-pass effect influence bioavailability if the metabolite was active?

Answer 48

It could increase the bioavailability (if more active) or cause the bioavailability to decrease slightly (if somewhat active).

Question 49

What is enterohepatic recycling?

Answer 49

The process by which bile in the GI system is recycled.

Question 50

How does enterohepatic recycling affect drug absorption/elimination?

Answer 50

- Drugs eliminated by bile secretion can be reabsorbed along with the bile. - Once reabsorbed they can be separated from the bile, uneliminating them. - Reabsorbed drugs can then enter systemic circulation.

Question 51

What are efflux pumps? How can they inhibit drug absorption?

Answer 51

Pumps which remove molecules from inside a cell, decreasing its concentration. They can remove a drug as it is being absorbed, decreasing and even reversing the rate of absorption.

Question 52

What does PGP stand for? What is it and why is it important?

Answer 52

PGP: P-Glycoprotein It is an efflux pump located on the BBB and GI organs that removes molecules from within a cell. It's important because PGP is responsible for the poor bioavailability and low CNS concentrations of numerous drugs.

Question 53

What main areas of the body contain PGPs?

Answer 53

- Liver - Kidneys - Intestines - BBB

Question 54

Explain why PGP inhibitors are so important

Answer 54

They inhibit PGP pumps, allowing for drugs that are targeted by the pumps to reach therapeutic levels inside cells.

Question 55

What are some of the main roles of a dosage form? [4 minimum]

Answer 55

- Enable accurate dosing - Protect the drug (storage and admin) - Conceal taste or odour - Improve delivery efficacy (for certain routes or patients) - Modify delivery time

Question 56

How will the standard and delayed absorption form of a drug differ in their pharmacokinetics?

Answer 56

Delayed will have a higher Tmax, same Cmax.

Question 57

What feature defines 1st order absorption?

Answer 57

The greater the amount to be absorbed (drug quantity), the faster the absorption rate.

Question 58

What feature defines 0th order absorption?

Answer 58

The amount of drug absorbed is constant. No change in absorption rate.