Dugga 2 - chapter 14

Question 1

What is ADME?

Answer 1

Absorption distribution metabolism excretion

Question 2

Polar drugs do not pass the ???

Answer 2

Gut wall nor act intracellularly if injected

Question 3

Very hydrophobic drugs will ???? in the gut and poorly be absorbed

Answer 3

dissolve in fat globules

Question 4

What is the partition coefficient (P)?

Answer 4

P = Concentration of drug in octanol / Concentration of drug in aqueous solution.

Question 5

What is LogD

Answer 5

Logaritm of relative distribution of all species of the drug, both ionized and un ionized

Question 6

What affects absorption and oral bioavaliability?

Answer 6

• hydrophilic/hydrophobic properties
• Flexibility

Question 7

What groups can be used in masking polar functional groups to decrease polarity?

Answer 7

• alkyl or acyl making
  alcohol into an ester or ether.
  carboxylic acid into an amide or ester

Question 8

Why is tioconazol (antifungal) only used on the skin?

Answer 8

Poorly soluable in blood since it is non-polar.

Question 9

How does fluconazol differ from tioconazol?

Answer 9

It is more polar due to its polar hydrocyl group and more polar heterocyclic rings

Question 10

Why is nitrogen-containing heterocycles added to drugs?

Answer 10

• It increases the polarity of the drug and makes it more water soluble.

Question 11

Why should you add a polar group so that it is still availble to interact with water when compound is bound to target?

Answer 11

Energy is not lost in desolvation once bound/binding to target.

Question 12

What if a compund is too polar? What can you do?

Answer 12

Remove polar group

Question 13

What does methylene shuffel mean?

Answer 13

Increasing the size of one alkyl group and decreasing the size of another

Question 14

What substituent was removed in creating anticancer drug relugolix and making it less hydrophobic resulting in no longer inhibit p450?

Answer 14

Phenyl

Question 15

Addition of chloro, fluoro substituents will make the compound more hydrophobic or hydrophilic?

Answer 15

Hydrophobic

Question 16

Extra N-alkyl groups will …?

Answer 16

Contribute with a electron donating effect resulting in increasing the basicity.

Question 17

Too long aklyl chain in N-alkyl groups may result in …?

Answer 17

increasing the steric bulk around the nitrogen hindering the water molecules from solvating the ionized form of the base and prevents stabilization of the ion ==> lowers basicity.

This can be used to wrap up a basic nitrogen within a ring to lower bacisity.

Question 18

Mention other structural variations that affect pKa.

Answer 18

For aromatic amine or aromatic carboxylic acid an electron-withdrawing substituent can be added to the ring to vary pKa. OBS position is more important than closeness

For non aromatic system the same thing will alter the pka of an ionizable group if the electron withdrawing substiuent sits close to the group

Question 19

An ester prodrug can mask … making it less polar so it doesn’t ionize the compound.

Answer 19

Carboxylic acid

Question 20

What is 5-substituted tetrazole?

Answer 20

A bio-isosthere used to replace carboxylic acid. The tetrazole anion is 10 times as lipohilic as the carboxylate anion ==> increased drug absorption

Question 21

Mention a bioisostere for phenol

Answer 21

Heterocycklic ring with NH group

Question 22

What are the ways we can make drugs more resistant to chemical and enzymatic degradation?

Answer 22

• Steric sheilds
• Electronic effects of bio-isosteres and substituents
• Steric and electronic modifications
• Metabolic blockers
• Removal or replacement of susceptible metabolic groups
• Group shifts
• Ring variation and ring substituents

Question 23

What are the ways we can make drugs more resistant to drug metabolism?

Answer 23

• Introducing metabolically susceptible groups
• Self-destruct drugs

Question 24

What are the differnt targets for targeting drugs?

Answer 24

• Tumor cells
• Gastrointestinal infections
• Targets in the cell membrane
• Antibacterial agents

Question 25

Mention a method that is used to target tumor cells but not normal cells.

Answer 25

• Attach the active drug to important building block molecules that is needed in a large amounts by the rapidly dividing tumor cells ex uracil mustard
• Attach the drug to monocologal antibodies.
• ADEPT

Question 26

What kind of drugs are used for Gastrointestinal infections and why?

Answer 26

Ionized drugs because they doesn’t pass the gut wall/cell membranes

Question 27

What is special with drugs that target targets in the cell membrane?

Answer 27

They are attached to membrane tethers so that they are anchored in the membrane.

ex inhibition of B-secretase treating AD

Question 28

What type of drugs target siderophores

Answer 28

Antibacterial drugs that mimics sidophores to enter the bacterial cell

Question 29

What compounds are higher risk of toxic metabolites?

Answer 29

Aromatic nito groups and aromatic amines.

Question 30

What is the halogen substitutients were used in minimizing the toxicity of UK 47265 creating fluconazol?

Answer 30

Cl were replaced with F which is not as good leaving group ==> less toxic!

Question 31

What is a prodrug

Answer 31

A drug that are inactive as themselves but are converted in the body to the active drug. Usually a metabolic enzyme is involved in converting the prodrug to the active drug.

Question 32

What are the benifits of prodrugs?

Answer 32

Tackels:
- acid sensitivity
- Poor membrane permeability
- drug toxicity
- Bad taste
- Short duration of action

Question 33

What are an examples of a prodrug that improve membrane permeability?

Answer 33

• Ester prodrugs that are hydrolysed by esterase enzymes. Important in masking awkward functional groups important to binding but hindering the drug from passing the gut wall. The ester is less polar than the important functional group.

ex: pivampicillin = a penicillin prodrug

• N-Methylated prodrugs

Question 34

In what other way than enzymatic can a prodrug be activated?

Answer 34

By external light

Question 35

How can you make a ester a better prodrug?

Answer 35

Introduce an electron withdrawing group making it more susceptible to hydrolysis. This stabalizes the alkooxide LG trhough inductive effect.

Make an extented ester to avoid failed hydrolysis because of bulky groups

Question 36

What is one pro drug that uses the trojan horse approach?

Answer 36

Levodopa that is a prodrug for dopamine. Levodopa is polar but an amino acid and can use transport proteins to cross the cell membrane and pass the Blood brain barrier. In the brain decarboxylase enzyme removes the acid group and generates dopamine.

Question 37

Prodrug can be used masking drug toxicity and side effects give two examples.

Answer 37

Asprin - Phenol on salicylc acid causes gastic bleeding. Masking the phenol as an ester (asprin) makes the passage through the gut harmless. Once in the blood streem the ester is hydrolysed to free the active drug.

Cyclophosphamide - a anticancer drug, that uses masking to only get activated at its target, the liver.

Question 38

Prodrugs can prolong drug activity by

Answer 38

• Slower distribution/release of the drug in the body, not so strong immune response.
• The prodrug is lipophilic and stored in fatty tissue, slow release in the blood supply ex antimalarian drugs or fluphenazine

Question 39

How can a prodrugs that lower water solubility make the drug easier to take?

Answer 39

Prevent the drug from dissolving on the tongue and thereby avoid bad taste.

Question 40

Prodrugs to improve water solubility

Answer 40

• Improve gut absorption, too non-polar drugs can’t interact with the gut wall