BMP: Drug Design 8

Question 1

1. What is a prodrug?
2. What are the purpose of them?

Answer 1

1. An inactive precursor of a drug, converted into its active form in the body by metabolic processes
2. Desgined to maximise the effectiveness of the active drug and often employed to tackle problems e.g. solubility, poor membrane permeability, drug toxicity, bad taste or short duration of actino

Question 2

Describe the process of drug absorption

Answer 2

1. Drug give orally
2. Deug enters GI tract: Mouth, throat, stomach and intestines. Acid labile drugs (e.g. insulin) cannot be given orally
3. If drug survives stomach it enters the upper intestine in whihc it must penetrate the GUT wall to be absorbed into the blood
4. The drug is then transported to the liver where it may be metabolised (1st pass) ormaymove onto its target site

Question 3

What properties of drugs are required to allow oral administration?

Answer 3

Not acid labile, good lipophilicty balance and resistancce to stmomach and liver enzymes

Question 4

What are 2 main things which drugs do?

Answer 4

Increase water solubility

Increase membrane permeability

Question 5

Give an example of a prodrug which has had its water solublity increased.

Why might this be useful?

Answer 5

• Chloramphenicol is poorly water soluble. Conversion to its succinate ester by addition of carboxylic acid groups improves water sol
• When the ester is hydroysised in vivo it produces chloroamphenicol and succinic acid
• Increasing water solubility of prodrugs has proven to reduce pain insome injectables

Question 6

Why is it important for drugs to have some water solubility?

Answer 6

• If not they will dissolve in adipose tissue and fail to interact with gut wall to be absorbed
• e.g. Oestron (HRT) is poorly water solubilty. Using lysine ester prodrug imoprves water solubility and absorption
• Hydroysis yields AA lysine and oestron

Question 7

Some drugs may be have polar groupe e.g. COOH vital in binding, however make the drug too polar for absotpion. How can this be avoidec?

Answer 7

Masked using ester, then upon entery into cell is cleaved my enzymes to yield the active drug

Question 8

What is an example a prodrug which has increased membrane permebailty

Answer 8

Pivampicillin

This is an extended esterthat contains a second ester grouup

Question 9

Why are convertional monoesters preped for e.g. methanol not suitable for this contex?

Answer 9

They become hidden from the esterases by the penicillin nucleus

Question 10

Not all ester groups hydrolysise with equal efficency. How can it be altered?

Answer 10

Addition of EWG to the alcohol component of the ester. These make esters more suspeptible to hydrolyssi.

It makes the alcohol a better leaving group by stabilising the negtaive charge on the oxygen atom

Question 11

What is dipivefrin a prodrug for? what does it do?

Answer 11

For antiglaucoma drug epinephrine

allows for greater corneal permeability and subsequently hydrolysed by corneal and aqueous humor esterases to liberate epinephrine

Question 12

What is another approach to improve membrane permeabilit?

Give an example

Answer 12

Trojan horse approach

Another method to transport drugsacorss the cell membrane is to take advatafe of carrier proteins in the cell wall

L-Dopa is a prodrug for dopamine used to treat parkinsons. Dopamine itself is too polar to cross the BBB. Coversion of dopamine to L-Dopa is transported across the the BBB b carrier proteins

Question 13

Bioprecursor Prodrugs – oxidative bioactivation

Answer 13

• N-Dealkylation
  
  • The open ring analogs of alprazolam (anxiolytic) and triazolam (sedative),
  • which are members of the benzodiazepine family, undergo N-dealkyation
  • catalysed by Cytochrome P450 followed by spontaneous cyclisation.
• Epoxidation
  
  • Carbamazepine, used in the treatment of epilepsy, is metabolically
  • transformed to the active epoxide derivative.