Week 7: Workshop 1 – Prodrug strategies in drug development

Question 1

What is CYP450?

Answer 1

Major metabolisizing enzyme in the liver

Question 2

What factors do you consider when selecting a route of administration?

Answer 2

• molecular properties of the drug
• physiological nature of the route
• patient compilance
• onset of action
• the condition being treated
• systemic or local effect (side effects)
• metabolism

Question 3

What is a prodrug?

Answer 3

A prodrug is a molecule with little or no pharmacological activity that is converted to the active parent drug in vivo by enzymatic or chemical reactions or by a combination of the two.

Question 4

What are the requirements for a drug to be absorbed through the mucosal membranes that line the gut?

Answer 4

Must be in its lipophilic unionised from to partition out of the aqueous medium

Question 5

What are the alternative administartion methods if oral administrtion and absorption is not appropriate?

Answer 5

• Rectal
• Vaginal
• Topical
• Buccal/ Sublingual
• Injection
• Respiratory
• Chemically modify the drug

Question 6

What is resporatory administartion?

Answer 6

Local administration by aerosols to the lungs eg salbuatamol, nasal steroids

Question 7

What is rectal administartion?

Answer 7

Local administration, and an alternative systemic route that avoids degrading pH and enzymes (pepsin, gastrin), although the absorbing surface is smaller.

Question 8

How do you chemically modify a drug?

Answer 8

• Design out problemst of bioavailability
• Considre pharmacodynamic/ Pharmacokinetic balance eg steroids
• Pro drug design strategy

Question 8

How do you chemically modify a drug?

Answer 8

• Design out problemst of bioavailability
• Considre pharmacodynamic/ Pharmacokinetic balance eg steroids
• Pro drug design strategy

Question 9

Why are pro drugs designed?

Answer 9

To control the ADME of the drug

Question 10

What determines how much of a drug is absorbed?

Answer 10

• LogP
• LogD

Question 11

What is the absorption phase of a dose-respose curve influenced by?

Answer 11

pKa and log P of a drug.

Question 12

What is topical administartion

Answer 12

Local administration with creams, ointments and drops. Systemic delivery of lipophilic drugs by transdermal patches (avoids spiking).

Question 13

Describe buccal/ sublingual delivery

Answer 13

Fast onset of action that avoids first-pass metabolism – requires high Log P properties

Question 14

Describe injections

Answer 14

• i.v. for rapid onset, requires water soluble forms. Cant have high logP because has to be soluble in water.
• i.m can be used for sustained-release depot injections, requires lipid-soluble forms.

Question 15

How can drugs be chemically modified to improve absorption?

Answer 15

• Improve bioavaiablity problems by modifying lipophilicity/ hydrophilicity, enhance stability, block metabolic transformations
• always consider pharmacokinetic/ pharmacodynamic balance
• Design the drugs as pro drugs - temporary structural modification, labile functional groups mask problem being overcome, Parent drug released once absorbed

Question 16

What is the active form of enalipril?

Answer 16

Enalaprilat

Question 17

How is enalapril converted to enaliprilat?

Answer 17

By liver esterases

Question 18

What is the logP of enalapril?

Answer 18

0.7 - lipophilic, so good absorption

Question 19

What is the logP of enaliprilat?

Answer 19

-0.5 so poor absoprtion

Question 20

What is the IC50 of enalipril

Answer 20

1.2

Question 21

What is the IC50 of enaliprilat?

Answer 21

0.0012 - good pharmacodynamic activity

Question 22

What is the ester carbonyl group?

Answer 22

A weak electrophile and relies on attack by a weakly nucleophilic water molecule

Question 23

What is an esterase?

Answer 23

Enzymes used to catylyse the hydrolysis of ester groups.

Question 24

What does the active site of an esterase contain?

Answer 24

Asp, His, Ser residue

Question 25

What does asp in an esterase act as?

Answer 25

Base - Proton acceptor

Question 26

What does His in an esterase act as?

Answer 26

Acid - Proton donor, donates proton to carbonyl group

Question 27

What does Ser in an esterase act as?

Answer 27

strong nucleophile

Question 28

When are IV injections required?

Answer 28

• Low bioavaibility of other routes
• Unable to dose by other routes
• Fast onset needed

Question 29

What physicochemical properties must a drug have to be administered by intravenous injection?

Answer 29

• Good aqueous solubility
• Low logP, logD
• Low tendancy to precipitate in blood plasma

Question 30

What is IV promethazine used to treat?

Answer 30

Anaphylaxis

Question 31

What is IV doxapram used to treat?

Answer 31

Respiratory failure

Question 32

What is IV diclofenac used to treat?

Answer 32

Inflammation

Question 33

What is the target drug for promethazine?

Answer 33

α1-adrenergic receptor
(vasodilation)

Question 34

What is the target drug for doxapram?

Answer 34

Potassium channel blocker
(respiratory stimulant)

Question 35

What is the target drug for diclofenac?

Answer 35

COX enzymes (COX-2)
(reduced inflammatory response)

Question 36

What is the pKa of promethazine?

Answer 36

9

Question 37

What is the pKa of doxapram?

Answer 37

8

Question 38

What is the pKa of diclofenac?

Answer 38

4

Question 39

What state would promethazine need to be formulates as for an IV injection?

Answer 39

Promethazine HCl

Question 40

What state would doxapram need to be formulates as for an IV injection?

Answer 40

Doxapram HCl

Question 41

What state would diclofenac need to be formulates as for an IV injection?

Answer 41

Diclofenac sodium

Question 42

What do acute hypersensitivity reactions require?

Answer 42

i.v. administration of hydrocortisone

Question 43

What may be required for anaphylactic shock or angioeadema of the upper respiraory tract?

Answer 43

100-300mg of hydrocortisone

Question 44

What is the salt form of hydrocortisone?

Answer 44

Hydrocortisone Sodium Succinate