Solubility and partitioning of drugs

Question 1

What are the barriers that a drug has to cross before it becomes effective?

Answer 1

GIT

BBB

Question 2

Why are biological membranes hydrophobic in nature?

Answer 2

Because they are composed of phospholipids containing long hydrobcarbon chains

Question 3

What must a drug do to succeed in its mission?

Answer 3

Pass from the aq solution of the EXTRACELLULAR fluid to the aq solution of the INTRACELLULAR fluid by crossing the lipid membrane

Question 4

What are the properties of some organic solvents (e.g. n-octanol, cyclohexane) thought to resemble?

Answer 4

Similar properties of a lipid bilayer membrane. This suggests that distribution of drugs into hydrophobic organic media stimulates their ability to passively diffuse across biological membranes

Question 5

What is partitioning?

Answer 5

The movement (or redistribution) of organic compounds from one liquid to another

Question 6

What happens if an excess of an organic compound is added to a mixture of two immiscible liquids?

Answer 6

It will partition itself between the two liquids so that each becomes saturated

Question 7

What happens if the amount of compound added is not enough to saturate the solutions?

Answer 7

It will be distributed between the two immiscible liquids according to a definite concentration ratio:
Corg -> Caq

Question 8

What is the partition coefficient (P)?

Answer 8

A constant, which is the ratio of concentration of compound in organic phase to the concentration in aq phase at EQUILIBRIUM

Question 9

What is the equation for P?

Answer 9

P = Corg/Caq

Question 10

What is the TRUE partition coefficient?

Answer 10

The partition coefficient of UNIONISED drug

Question 11

What does it mean if Ptrue > 1?

Answer 11

Then Corg > Caq and the compound is HYDROPHOBIC (lipophilic)

Question 12

What does it mean if Ptrue < 1?

Answer 12

then Corg < Caq and the compound is HYDROPHILIC (lipophobic/polar)

Question 13

What does LogP = 1 means?

Answer 13

P = 10 and Corg:Caq = 10:1

Question 14

What does LogP = 0 mean?

Answer 14

P=1 and Corg:Caq = 1:1

Question 15

What does P= -1 mean?

Answer 15

P= 0.1 and Corg:Caq = 1:10

Question 16

What can P be used to predict?

Answer 16

the absorption, distribution and elimination of drugs within the body

Question 17

What is the Hansch-Fujita parameter?

Answer 17

They describe the contribution of various functional groups to the lipophilicity of a compound

Question 18

What are the hydrophobic functional groups (+)?

Answer 18

Aromatic hyrdocarbons
Aliphatic hydrocarbons
Halogens

Question 19

What will happen to P if there is a predominance of hydrophobic (+) groups?

Answer 19

Increase - making molecule more lipid soluble and more able to pass through the lipid membrane

Question 20

What are the hydrophilic (-) functional groups?

Answer 20

Hydroxyl groups
Carboxyl groups
Amines
Ether
Amide

Question 21

What will happen to P if there is a predominance of hydrophilic groups (-)?

Answer 21

Decrease - making molecule less lipid soluble and less able to pass through the lipid membrane

Question 22

How does the permeability of a drug in the unionised form differ from that of the ionised form?

Answer 22

Permeability of the unionised form of a drug across a phospholipid membrane by passive diffusion is 10^8 higher

Question 23

Should a drug be in the ionised or unionised form at the membrane surface to permeate the membrane by passive diffusion?

Answer 23

Uncharges (i.e. unionised)

Question 24

What effects the concentration of the compound passing through the membrane barrier?

Answer 24

The % of the compound that is unionised

Question 25

What controls the % of the unionised compound?

Answer 25

pKa of compound and pH of solution

Question 26

For weak acids and bases, how does P vary?

Answer 26

Varies depending upon the pH at which it is measured (APPARENT P)

Question 27

Papparent is sometimes referred to as what?

Answer 27

D or Distribution coefficient

Question 28

What is Papparent dependent on?

Answer 28

the proportion of unionised form of the drug present in solution

Question 29

How is Papparent calculated?

Answer 29

Papp = Ptrue x funionised

Question 30

What is funionised?

Answer 30

The fraction of the total amount of drug unionised at a certain pH

Question 31

What does is mean if funionised = 1?

Answer 31

Then Papp = Ptrue

Question 32

What is funionised dependent upon?

Answer 32

The pH of the aq solution and the pKa of the drug

Question 33

If drug is only absorbed in the small intestine there will be a delay in onset of action. Why?

Answer 33

Because the drug has to pass through the stomach first

Question 34

When should patients take antihistamines for travel sickness?

Answer 34

At least one hour before travelling

Question 35

Drugs can be _______ in the kidneys rather than excreted.

Answer 35

reabsorbed

Question 36

How is it possible to control reabsorption of drugs from the kidney tubule and accelerate excretion?

Answer 36

If the reabsorption happens through passive diffusion via unionised drug form, the same partitioning rules can be applied

Question 37

Acidic drugs are reabsorbed best from _______ urine

Answer 37

Acidic

Question 38

If the drug taken in overdose is a weak acid then the reabsorption can be minimised by _______ the urine

Answer 38

basifying

Question 39

What happens to acidic drugs in forced base diuresis in terms of reabsorption and clearance?

Answer 39

The reabsorption decreases and the clearance is more rapid

Question 40

Basic drugs are reabsorbed best from _______ urine

Answer 40

Alkaline

Question 41

If the drug taken in overdose is a weak base reabsorption can be minimised by _______ the urine

Answer 41

acidifying

Question 42

What happens to basic drugs in forced acid diuresis in terms of reabsorption and clearance?

Answer 42

decrease in reabsorption and more rapid clearance