Lecture 3: Drug Absorption And Distribution

Question 1

What is drug disposition?

Answer 1

Drug disposition can be consider e to be the processes a drug is subjected to by the body upon administration

Question 2

What are the processes of drug disposition?

Answer 2

Absorption Distribution Metabolism Excretion

Question 3

What is excretion also known as?

Answer 3

Removal from body

Question 4

What is the most common route of drug administration?

Answer 4

Oral or rectal

Question 5

Why is the oral or rectal route of drug administration most common?

Answer 5

Fewest complication

Question 6

Most drug movement is not

Answer 6

Unidirectional

Question 7

What are the drug administration routes?

Answer 7

Oral, rectal, percutaneous, intravenous, intramuscular, intrathecal, inhalational

Question 8

What are the drug elimination routes?

Answer 8

Urine, faeces, milk, sweat, expired air

Question 9

What can the lung serve as?

Answer 9

Route of both administration and elimination

Question 10

What 2 ways can the drug molecules move around the body?

Answer 10

Bulk flow (I.e. bloodstream, lymphatic, cerebrospinal fluid) Diffusion (I.e. molecule by molecule over short distances)

Question 11

What is the ability to cross the hydrophobic diffusion barriers strongly influenced by?

Answer 11

Lipid solubility

Question 12

What is the concept of Bioavailability?

Answer 12

The fraction (F) or the administered dose that reaches the systemic circulation

Question 13

What is the bioavailability of an intravenous injection?

Answer 13

F=1, Bioavailability=100%

Question 14

What is the bioavailability for other routes?

Answer 14

Less than 1

Question 15

What does a bioavailability of less than 1 reflect?

Answer 15

Gastric instability of drug First pass metabolism Reduced absorption into the circulation

Question 16

What are the factors affecting drug absorption?

Answer 16

Gastric motility Area of absorbing surface Blood flow at absorbing surface Ingestion of food Plasma protein Binding Nature of the drug Ionised/ non ionised form

Question 17

Gastric motility

Answer 17

Affected by disease/food How quickly the drug/ substance passes through the GI tract

Question 18

Area of absorbing surface

Answer 18

Large surface area means more absorption across any particular membrane

Question 19

Blood flow at absorbing surface

Answer 19

Affected by food/exercise Direct blood flow away from GI slowing digestion towards lungs/heart and exercising muscles

Question 20

Ingestion of food

Answer 20

Possible interactions

Question 21

Plasma protein binding

Answer 21

Equilibrium between free drug and plasma bound membrane

Question 22

Nature of the drug. Ionised/ non ionised form

Answer 22

Most are either weak acids or weak bases Exhibit PH-dependent ionisation - dependent on PH in different areas of the body Ionised species are not lipid soluble

Question 23

What sort of drugs diffuse through aqueous channels?

Answer 23

Water soluble drugs

Question 24

What is the most important method of absorption across a membrane?

Answer 24

Diffusion across a membrane

Question 25

Diffusion through aqueous pores/ Ion channels

Answer 25

Movement occurs down a concentration gradient The membrane contains small pores which allow water soluble molecules of less than 100Da through

Question 26

Examples of agents that use diffusion through aqeuous pores / Ion channels

Answer 26

Lithium - small monovalent ion

Question 27

Why is diffusion through aqeuous pores/ Ion channels not a major route for drug permeation?

Answer 27

Most drugs aren’t small enough

Question 28

Carrier mediated transport

Answer 28

Active transport/ facilitates diffusion

Question 29

What are the important sites for carrier mediated transport?

Answer 29

Important stores for such transfer, from a pharmacokinetic point of view include: renal tubule Blood brain barrier are important barriers drug must cross to be absorbed Gastrointestinal tract

Question 30

What can limit the rate of permutation for carrier mediated transport?

Answer 30

Saturation of transporters

Question 31

Pinocytosis

Answer 31

Concerned with the uptake of marcomolecules Engulfing membrane across very large molecules

Question 32

What size of drugs can enter via pinocytosis?

Answer 32

Drugs of large molecular weight (1000Da or more) can permeate via this route

Question 33

What is an example of of a drug that can permeate through pinocytosis?

Answer 33

Insulin crossing the blood brain barrier

Question 34

How have researchers tried to incorporate pinocytosis into drug uptake?

Answer 34

Incorporating the drug into lipid liposomes

Question 35

What ride drugs does diffusion through lipid Membranes allow for?

Answer 35

Only allow small lipid soluble non-polar drugs through

Question 36

What size drugs does diffusion through lipid Membranes allow for?

Answer 36

Surface area and blood flow. Degree of permeation is determined through Ficks Law Knowing the percentage of drug ionised

Question 37

What factors of Ficks Law are directly related to rate?

Answer 37

dQ/day - amount of drug diffusing with time Pk - permeability constant A - membrane area C1/C2 - concentration of drug either side of the membrane

Question 38

What factors of Ficks Law are indirectly related to rate?

Answer 38

Membrane thickness

Question 39

What is the effect of PH on drug ionisation?

Answer 39

Important as it allows prediction of absorption Most drugs are either weak acids or weak bases

Question 40

What is PKA ?

Answer 40

Dissociation constant - equal to the PH at which 50% of the drug molecules are ionised

Question 41

What does degree of ionisation give rise to?

Answer 41

Ion trapping

Question 42

What does a high degree of ionisation mean?

Answer 42

Little crosses the membrane

Question 43

Treating drug overdose

Answer 43

Alkaline urine means drugs won’t pass to the nephron this fam be used in the case of aspirin overdose. Urine can be alkalinized e.g. with NAOH changing ionised/unionised ratio

Question 44

What is volume of distribution?

Answer 44

The volume of fluid required to contain the total amount of drug in the body at the same concentration as that present in the plasma

Question 45

What is Cp?

Answer 45

Plasma concentration

Question 46

How to calculate volume of distribution?

Answer 46

Vd = Dose/Cp

Question 47

What does it mean if you have high lipid solubility?

Answer 47

Higher amount of your compound partitions into the cell membrane Faster rate of movement across lipid soluble fell membrane and into the inside of the cell

Question 48

What makes up Fricks Law?

Answer 48

Steepness of the concentration gradient The surface area of the membrane across which diffusion is taking place The lipid solubility of the substance Membrane thickness

Question 49

Steepness of the concentration gradient

Answer 49

The bigger the concentration gradient, the steeper it is, the faster the rate of diffusion

Question 50

The surface area of membrane across which diffusion takes place

Answer 50

The larger the surface area, the greater the rate of diffusion

Question 51

The lipid solubility of the substance

Answer 51

The greater the lipid solubility of drug, the faster the substance can diffuse down its concentration gradient through lipid bilayer Smaller transmembrane concentration for insoluble lipid hence slower diffusion

Question 52

Membrane thickness

Answer 52

Thicker membrane means slower rate of diffusion Thinner membrane - fast rate of diffusion

Question 53

What is Ion trapping?

Answer 53

High PH of a drug that has relatively low PKA

Question 54

What are the 3 body compartments that a weak acid and a weak base would be distributed at equilibrium?

Answer 54

Plasma (PH 7.4) Alkaline urine (PH 8) Gastric juice ( PH 3)

Question 55

What does the ratio of ionised to unionised drug govern?

Answer 55

PKA is the drug and PH of that compartment

Question 56

What can cross the membrane?

Answer 56

Unionised species

Question 57

What cannot cross the membrane?

Answer 57

Ionised species

Question 58

How does drugs leave the circulation ?

Answer 58

Capillary filtration

Question 59

What are the different body compartments that the drug can distribute to?

Answer 59

Transceullar water Intracellular water Interstitial water Plasma water Fat