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Intro to Pharmacology > Effect of ionization on drug lipophilicity > Flashcards

Effect of ionization on drug lipophilicity Flashcards

1
Q

When a drug becomes ionized, this will _______ its solubility in water.
Why?

A

Increase solubility in water
B/C there will be a better solvation by ionic-dipole interaction between the ionized drug and water molecule.
Drug can better interact with water through hydrogen bonds, ionic interactions, etc.

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2
Q

If a protein is dissolved in water and salt is added, what occurs?

A

Salting out. The protein precipitates out of solution.

This is because the salt takes out water molecules surrounding the compound

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3
Q

Because most drugs are ionizable at different body pH ranges, the _________ must be taken into consideration when we are about to synthesize or develop certain drugs.

A

% ionization

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4
Q

__________ will determine from where the drug will be absorbed and what target tissue it will reach.

A

Lipophilicity

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5
Q

Unionized –> no _____ –> more _______ –> can ______ across the membrane

A

charge
lipophilic
partition

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6
Q

How does lipophilicity affect what target tissue the drug will reach?

A

In some tissues, the lipid bilayer will have different porosity and will further determine where the drug is absorbed.

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7
Q

The unionized form of an acid is also called the ______ form.
The unionized form of a base is also called the ________.

A

protonated

unprotonated

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8
Q

Solubility:
The property of a _____, ______ or ________ chemical substance called a _______ to dissolve in a solid, liquid, or gaseous solvent to form a __________ solution of the solute in the solvent.

A

liquid, solid, gaseous
solute
homogeneous

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9
Q

Solubility is a _______ property of the compound.

A

physical

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10
Q

The _______ of the solubility of a substance in a specific solvent is measured as the ________ __________ where adding more solute does not increase the concentration of the solution.

A

extent

saturation concentration

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11
Q

What are the most common ways to express solubility?

A

grams of solute per liter of solvent

Molarity - moles of solute per litre of solution

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12
Q

How can the formulation of biological compounds that are not dissolved well, particularly in water, be improved?

A
  • Create (form) a salt
  • Reduce particle sizes
  • Find and use a better solvent
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13
Q

Why does a reduction in particle sizes increase solubility?

A

Related to surface area.

Hydrogen bonds can be formed much more easily.

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14
Q

Why is changing the solvent not always a viable option for increasing solubility?

A

Food and drugs go hand in hand. So, needs to be safe, cannot always add alcohol, acetone or chloroform.

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15
Q

When changing the pH to increase solubility, what must be taken into account?

A

The drug needs to not be too corrosive.

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16
Q

Penicilin, in the free acid form, is not very soluble. How was this remedied?

A

Increased the solubility by changing it to the salt form - potassium form to be exact.

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17
Q

Other than simple solubility, for a drug to be effective in the body, what is important?

A

The drug has to be in a high enough plasma concentration.

The drug needs to not only be soluble, but able to partition well.

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18
Q

The most effective form of a drug will be both _______ and have a high _______ _________.

A

soluble

plasma concentration

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19
Q

If solubility needs to be increased for a drug. What is the first thing that a pharmaceutical company will do?

A

Grind the drug into smaller particles

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20
Q

What is tween?

A

Compound that acts as a detergent - allows a powder to wet easier.
Tween acts as a detergent to make the fine particles interact with water more efficiently.

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21
Q

Different brands may have different onsets of action. Why?

A

Due to the particle size of the different drugs/addition of tween.
They are the same formulation but different particle size.

22
Q

The partition coefficient is expressed as what?

A

P or logP (if large)

23
Q

What is the partition coefficient?

A

The ratio of concentrations of a compound in the two phases of a mixture of two immiscible solvents at equilibrium.

24
Q

What does immiscible mean (referring to liquids)?

A

Liquids not forming a homogeneous mixture when added together.

25
Q

What are the two immiscible solvents in pharmaceutical sciences, to determine P?

A

water and n-octanol

26
Q

What does n-octanol represent?

A

the lipid bi-layer of a cell memrbane

27
Q

Why is the partition coefficient based on two immiscible liquids? Why not more?

A

Because this is the simplest formulation.

One partition between two compartments.

28
Q

How is the partition coefficient determined?

A

Place drug in beaker containing both a buffer (aqueous phase) and n-octanol (organic phase).
Shake and leave it.
Drug redistributes in both.
Take sample from organic and aqueous phase.
Use mass spec and determine P.

29
Q

How is P calculated?

A

P = [Co]/[Cw]
or
LogP = Log [Co]/[Cw]

30
Q

The partition equation does not determine the effect of _____ on the lipophilicity of drugs.

A

ionization

31
Q

If P is _____ than 1 it partitions well into the lipid.

Conversely, if P is ______ than 1, it likes to stay in the aqueous phase.

A

larger

smaller

32
Q

A higher P value means higher ________.

We would expect to have a higher ______ _________ in that case.

A

lipophilicity

plasma concentration

33
Q

_____ can be used to predict the behaviour of a compound at all pH values, as long as we know ____.

A

Papp

P

34
Q

For acids, at pH values below _____, Papp = ___?

A

pka

P

35
Q

At pH values above the pKa, the value of Papp _______. Why?

A

decreases

Because the species is ionizing and moving into the aqueous layer

36
Q

What is the equation to calculate Papp?

A

Papp = P/ 1 + 10^(pH-pKa)

37
Q

For the Papp equation, if pH = pKa, what is the bottom term equal to?

A

2

38
Q

If the pH is above pKa, the Papp will be ______, the drug will be ______ and move to the _______ phase.

A

decreased
ionized
aqueous

39
Q

What is the Papp equation for bases?

A

Papp = P/1+10^(pKa-pH)

40
Q

For the acidic drug, RCOOH, which has a pKa of 4 and a P value of 200, what would Papp be in the stomach (pH - 2) and intestine (pH - 8)?
Where is the drug absorbed better?

A

Refer to notes

41
Q

Oral administration and absorption:
If a drug is to be absorbed through the ______ membranes that line the gut, then it must be in its ________ or ________ form to partition out of the aqueous medium.

A

mucosal

lipophilic or unionized

42
Q

The _______ ________ of the unionized form will also determined how much is absorbed.

A

Partition coefficient (P)

43
Q

The absorption phase of the dose-response curve is heavily influenced by the ____ and ____ of a drug.

A

pKa

logP

44
Q

What are Lipinski’s rule of five?

A 
Orally administered drugs must have:
- logP < 5
- No more than 10 hydrogen bond acceptors
- no more than 5 hydrogen bond donors
- A molecular weight less than 500 Da
(not more than 7 rotatable bonds)
45
Q

What is an addition to Lipinski’s rule of five?

A

An orally administered drug must have no more than 7 rotatable bonds.

46
Q

Why must an orally administered drug be less than 500 Da?

A

Can’t be too bulky, else it wont partition

47
Q

Why should there be no more than 7 rotatable bonds for an orally administered drug?

A

More constrained, better for receptor interaction

48
Q

For acids:
A high pKa means the species is predominantly _____, is a ____ proton donor, and a _____ acid.

A low pKa means the species is predominantly ______, is a _____ proton donor, and a _____ acid.

A

unionized, bad, weak

ionized, good, strong

49
Q

For acids:
pH < pKa by 2 units –> ___% unionized
pH > pKa by 2 units –> ___% unionized

A

99

0.99

50
Q

For bases:
A high pKa means the species is predominantly _____, is a ____ proton acceptor, and a _____ base.

A low pKa means the species is predominantly ______, is a _____ proton acceptor, and a _____ base.

A

ionized, good, strong

unionized, bad, weak

51
Q

For bases:
pH < pKa by 2 units –> ___% unionized
pH > pKa by 2 units –> ___% unionized

A

0.99

99

Intro to Pharmacology (23 decks)

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