Lecture 14

Question 1

using our knowledge of ionisation and lipophilicity, what can we predict?

Answer 1

drug distribution around the body, and all the ADME processes (apart from metabolism) as they are all based on diffusion

Question 2

What is the biological membrane made up of?

Answer 2

a bilayer of phospholipids where some proteins and transporters are embedded

membrane is semipermeable which only allows specific molecules to diffuse through

Question 3

why can lipid molecules penetrate easily

Answer 3

the bilayer is lipid in nature so lipid molecules can penetrate easily

Question 4

What is the major mechanism of drug transport?

Answer 4

passive diffusion

Question 5

what are the other mechanisms of drug transport?

Answer 5

active transport

facilitated diffusion

Question 6

is passive diffusion just through the bilayer?

Answer 6

no, it also goes through some channels

Question 7

How is the mechanism of resistance to cancer drug based on transport systems?

Answer 7

The anti-cancer Drug bring administered can reach tumour cells,
ButThe transporter pumps the drug out of the cells via active transport.
Therefore the drug cannot come to the DNA site, so patient is resistant
We can Try to block the transporter on the membrane so the anticancer drug can remain in the cell to bind to DNA

Question 8

What is the mechanism of passive diffusion?

Answer 8

Drug needs to be lipophilic, and has an affinity for the lipid bilayer.
Diffusion is about single molecules that means the drug needs to be dissolved, if not dissolved, it cannot diffuse well.
Need relatively high solubility, but how is this done when they are lipophilic? It is a balance.
If the solubility is too low it can be a rate limiting step
Passive diffusion is Concentration gradient driven

Question 9

How does the ionisation of the drug affect its transport into the cell?

Answer 9

if the drug is ionised, its lipophilicity is poor so cant diffuse via passive transport

Question 10

What is the pH partition theory?

Answer 10

PH changes the ionisation state, that means it changes the drug lipophilicity.
If pH changes the ionisation. The ionised drug cannot diffuse easily through the biological membrane.
Only the smaller molecules (less than 500MW)
But depends on administration route, for the skin the size can be bigger but need to be smaller than 1000
Small unionised molecules have no difficulty diffusing through

Question 11

What is lipophilicity good for?

Answer 11

penetration and diffusion of drug through the membrane

Question 12

What does it mean if the LogP is too high?

Answer 12

the drug is too lipophilic, thus water solubility will be too low, thus the concentration gradient it creates will be too low.

Question 13

what does it mean when the log p is too high?

Answer 13

drugs with high log p tend to have a protein bound to it, making it very hard to get through the membrane

Question 14

What is the rule of 5 we should consider when designing a new drug?

Answer 14

Log P should not be greater than 5 (otherwise water solubility will be too low)

Molecular weights should have no more than 5 hydrogen bond donors and no more than 10Hydrogen bond acceptors

Question 15

Why is pH important?

Answer 15

determines the ionisation state of the drug

Question 16

Is the equation positive for acids?

Answer 16

yes and it is negative for bases

Question 17

do drugs only have one ionisation state?

Answer 17

no some drugs can have 2 or more

Question 18

what is pka with respect to ionisation?

Answer 18

it is the pH where 50% of the drug is ionised and 50% is unionised

Question 19

For a base, if the pH is one unit higher than the pKa, will there be more or less ionisation?

Answer 19

there will be less ionisation,

Question 20

What can fick’s law be used to predict?

Answer 20

the absorption rate

dM = amount of drug that goes across the membrane

M/t = absorption rate

Question 21

What is the concentration gradient? / how is it calculated

Answer 21

it is the difference in the concentration / thickness

Question 22

What do we generally talk about when referring to absorption?

Answer 22

we talk about absorption through a hollow gut.

if the surface area is large, there will be a faster absorption rate

Question 23

Why can we simplify the equation so that it is only determined by the concentration of the drug in the gut?

Answer 23

because the concentration of tablet in the gut is much higher than that in the blood

Question 24

what does it mean when most drugs are class II?

Answer 24

they are permeable but less soluble (i.e. more lipophilic)

Question 25

why is drug permeability from the blood to the other tissue different?

Answer 25

we have a different parition barrier

Question 26

Why can ionised drugs be absorbed sometimes?

Answer 26

when unionised, the balance will be broken so the ionised drugs have to maintain the supply as the ratio is determined by the pH

Question 27

What can we use the euqation to predict?

Answer 27

how quickly the drug is absorbed.

Question 28

What factors of drug absorption are changing?

Answer 28

pH, membrane thickness, convection of the flow and the unstirred layers

Question 29

what happens if pH is different from the blood?

Answer 29

it may cause the blood to redistribute e.g. in the injection of a basic drug, you will find it accumulates in the GI tract.

Question 30

Why does a basic drug accumulate in the GI tract?

Answer 30

for a basic drug in an environment of pH 7.4, has a higher concentration of the unionised form.
As there is a high concentration of the drug after injection, it can diffuse through the GI tract where the pH is low

But the basic drug in the GI tract which is ionsed will not be able to penetrate through the membrane, so it accumulates over time

Question 31

How can we advise which drugs can be given to breast feeding women?

Answer 31

we know that the pH of milk is lower than in the blood, so basic drugs can easily accumulate in he milk

A basic drug in the plasma has a higher proportion which is unionsed so it can penetrate into the milk plasma membrane, however once in the milk environment, pH is lower so more of the drug becomes ionised

Question 32

Can an acidic drug with a pka of 4 penetrate into the milk?

Answer 32

an acidic drug at pH 7 will be ionised, so will not penetrate into the milk easily.

This is why if a mother has mastitis, its better to use a basic drug which will become ionised in the milk, so can be trapped in the milk

Question 33

What is the % of ionisation of a basic drug of pKa 7.24 in the plasma?

Answer 33

there will be 50% unionised in the plasma

this unionised form can penetrate anywhere including the milk

Question 34

What is ion trapping?

Answer 34

when there is a higher ionised ratio, so prevents the drug from penetrating elsewhere

Question 35

is an acidic drug or a basic drug better for breastfeeding?

Answer 35

acidic- as it wont get trapped in the milk phase, so will not drug the baby