Lecture 2 Oral Dosing and Absorption Concepts

Question 1

What does it means to have permeability rate-limits absorption?

Answer 1

Dissolution&raquo_space; Absorption

Question 2

What does it mean when Dissolution&raquo_space; Absorption?

Answer 2

Drug is hydrophillic; forms a solution rapidly

most of the drug has dissolved in GIT before an appreciable fraction has bben absorbed

Question 3

What does it mean to have dissolution rate-limits absorption?

Answer 3

Absorption&raquo_space; Dissolution

Question 4

What does it mean when Dissolution &laquo_space;Absorption?

Answer 4

Drug is hydrophobic; very little drug in solution at absorption site; any drug that is dissolved is absorbed ASAP
more common

Question 5

What is the difference between solubility and dissolution?

Answer 5

Solubility - intrinsic property

Dissolution - Overall system of drug; how fast the drug dissolves, etc.

Question 6

3 ways that the drug can be transported across GI membrane:

Answer 6

1. Passive transcellular
2. Paracellular
3. Facilitated transcellular
   no energy involved

Question 7

What are some factors that affect the transportation of drug across the GI membrane?

Answer 7

• Size of drug molecules

- Lipophilicity

Question 8

Paracellular permeability drops off sharply with MWs above ___g/mol

Answer 8

350g/mol

Question 9

Paracellular diffusion depends on the __ of the membrane

Answer 9

Rigidity of membrane

Question 10

More lipophilic the drug molecules, the ____ its permeability

Answer 10

greater permeability when drug molecules are more lipophilic

Question 11

What happens when the drug molecules are tooo lipophilic?

Answer 11

• Poorer aqueous solubility

- Greater propensity to bind to membrane transporters

Question 12

What is the pH-partition hypothesis?

Answer 12

pKa
Henderson-Hasselbalch equation
Drug molecules needs to be unionized in order to pass through

Question 13

4 reasons why most drugs are absorbed via SI rather than in gastric

Answer 13

1. SA 200m2 VS stomach 1m2
2. Blood flow in SI 1L/min VS stomach 150ml/min
3. Sink condition
4. More permeable membrane

Question 14

Since abs of all drugs is faster in intestine VS stomach, what is the controlling factor in the speed of drug abs even when it is given in solution?

Answer 14

Gastric emptying rate

Question 15

Why is gastric emptying important?

Answer 15

control the rate at which the drug is presented to the major site of absorption (upper SI); controls the onset along with the rate of abs

Question 16

What does intestinal motility determine?

Answer 16

Intestinal motility determines the residence time of the dosage form in the SI

Question 17

What will changes in motility alter?

Answer 17

Changes in motility could alter drug bioavailability depending on whether dissolution or permeability is the rate-limiting step

Question 18

How can we change the motility for dissolution rate limiting?

Answer 18

slow down motility (esp gastric emptying) allows for more complete dissolution and improves F (extent)

Question 19

How can we change the motility for permeability rate limiting?

Answer 19

Slow down motility to allow more time for absorption, thus compensates for poor permeability
Accelerated motility aggravates permeability problems

Question 20

GI motility when meal is taken

Answer 20

dec in GER (slow down)

Question 21

If solutions or suspensions of particles in GI motility

Answer 21

empty more rapidly, inc GER (speed up)

Question 22

If chunks of materials in GI motility

Answer 22

needs to be broken down before empyting, dec GER (slow down)

Question 23

If drugs are anticholinergic/narcotic analgesics, what happens to GER

Answer 23

Dec GER (slow down)

Question 24

If drugs like metoclopramide, what happens to GER?

Answer 24

Inc GER (speed up)

Question 25

Intake of food only affects

Answer 25

GER of stomach (transit time increases); | SI is unaffected by food, always 3-4h of absorption max

Question 26

When GER is reduced, what happens to the Cmax and T max

Answer 26

Cmax lowers, Tmax prolongs | reduction in systemic absorption

Question 27

Cmax and Tmax changes cannot conclude the extent of absorption is affected. Which term does?

Answer 27

AUCtotal

Question 28

How does the surface area per unit length changes along the intestine?

Answer 28

decreases from duodenum to rectum

Question 29

Where are the changes in tightness of junction (electrical resistance)

Answer 29

Higher in colon than SI | must be <350g/mol by paracellular mode

Question 30

How is the distribution like for metabolic enzymes and transporters in the GIT?

Answer 30

Distributed variably throughout GIT | e.g. PGP efflux pump's activity increases along GIT

Question 31

Where are the anaerobic microbes abundant?

Answer 31

Colon

Question 32

How does the pH vary along the intestine?

Answer 32

pH 6.6 (proximal SI) pH 7.5 (terminal ileum) pH 6.4 (caecum) pH 7.0 (descending colon)

Question 33

What is the mean transit time for SI and large bowel?

Answer 33

3-4hrs (SI) | 10-36hr (large bowel)

Question 34

Where does the absorption of less permeable drugs occur?

Answer 34

within SI even though drugs spend longer time in colon

Question 35

What are the properties of drugs with low Foral?

Answer 35

F = 0.005 -0.14 Polar, MW >400g/mol excessively variable oral abs, some given parenterally

Question 36

How do you define decrease in extent of abs?

Answer 36

dec Cmax, dec AUC

Question 37

GER impacts which term; Tmax or Cmax?

Answer 37

Tmax

Question 38

Formula for oral systemic bioavailability

Answer 38

Ff x Fg x Fh Ff: enters intestinal tissues Fg: reaches portal vein Fh: reaches liver

Question 39

What are the factors involved in drugs which are entering low impedance by porous capillary membrane (large fenestrations) in muscle and SC tissues?

Answer 39

1. Charge or uncharged 2. Degree of ionisation 3. Mol size (up to 5000g/mol)

Question 40

Which muscle group does more blood supply go to? | Deltoid or gluteal?

Answer 40

Deltoid >> gluteal

Question 41

Which site of adm supply more blood? IM or SC?

Answer 41

Higher blood supply to muscles IM than SC fats

Question 42

What can reduce blood flow, thereby reducing rate of absorption?

Answer 42

- Vasoconstrictor | - Shock

Question 43

What can increase blood flow, thus increasing rate of abs?

Answer 43

- Heat, fever, exercise

Question 44

Absorption of drug in solution from muscle and SC tissue is what type of rate-limited?

Answer 44

perfusion rate-limited