44- proton pump

Question 1

what is the proton pump

Answer 1

enzyme + Pore structure that spans the membranes of parietal cells. Pore structure that spans the membranes of parietal cells

Question 2

what are parietal cells

Answer 2

are the cells lining the stomach that produce acid

Question 3

what is the difference between H2 and proton pump inhibitor

Question 3

what is the difference between H2 and proton pump inhibitor

Answer 3

• H2 antagonist blocks histamine
  
  • Gastrin (hormone) also stimulates increase in stomach acid
  • Acetylcholine (neurotransmitter) acts like a hormone to increase stomach acid
  • H2 antagonism only gives partial reduction in HCl
  • H2 cannot completely stop acid production because those other two things could interfere
• Proton pump inhibitor would stop all acid production

Question 4

how is proton pump an ATPase, what does the hydrolysis of ATP contribute to the cell

Answer 4

• ATPase
  
  • Enzyme that converts ATP to ADP
• Hydrolysis of ATP provides energy for other jobs
  
  • Moves H+ from cells to stomach lumen
  • Moves K+ from stomach to cells
• Ratio of H+ in cells to H+ in stomach
  
  • 1 : 10^6
  • high gradient of protons
• ATP provides energy to drive against H+ gradient

Question 5

what does the drug target in the proton pump

Answer 5

Inhibit ATP hydrolysis to inhibit the enzyme

Question 6

outline the discovery of the proton pump enzyme

Answer 6

• Enzyme characterized
• Inhibition mechanism elucidated
• Lead compound identified by HTS

Question 7

how does the lead compound turn into its active form

Answer 7

under pH 2 it will undergo a chain of reactions turning it into a permanent cation

Question 8

what is the inhibition mechanism for the drug

Answer 8

look at notes

Question 9

how does the bioavailability of the drug give selective amplification

Answer 9

• Basicity of benzimidazole is low
  
  • Only protonated below pH 2
    
    • only in the stomach
  • The only place in the body this acidic is in the caniliculi
• Drug circulates in the body but cannot become protonated
  
  • cannot do any reactions with anything else in the body
• Protonation in caniliculi “traps” drug in caniliculi
• Protonation activates drug

Question 10

how does the drug become trapped in the stomach

Answer 10

• in the stomach cell it becomes protonated and cannot become neutral, traps inside the stomach
• le chatelier’s principle applies allowing it to concentrate in the tummy

Question 11

what drug form is required for selective delivery

Answer 11

• pill
• need to find a drug that will selectively deliver it to the body and avoid it from coming into contact with the stomach acid. it needs to get to the specific location
• Stomach acid converts drug to a very reactive compound
  
  • Will react with any nearby molecule
  • Reaction permanently “disables” the drug

Question 12

what are the requirements for the pill

Answer 12

• Must avoid acid activation in stomach lumen
  
  • Protect pill from stomach acid
• want the drug to react at the caniliculi
• Want activated drug only in region of canaliculi (stomach lining)

Question 13

what special feature do the pills have

Answer 13

• Specialized coating stable to acid
  
  • Prevent pills from dissolving in the stomach
• Coating dissolves at higher pH
  
  • Drug dissolves and absorbs in intestine
• Fatty acids, waxes, plastics, shellac
  
  • stable at low pH, removed at high pH

Question 14

what is omeprazole

Answer 14

• delayed-release drug (acid reducer)

- prilosec is the brand name

Question 15

how did the drug company for prilosec use a market share extension

Answer 15

• Patent expiry in 2001 allows others to make and sell the drug
  
  • Company will lose market share
• Protect market share by using a chiral switch
  
  • isn’t used very often but was very successful here

Question 16

in which three ways do enantiomers act differently in the body

Answer 16

• Efficacy
• Side effects
• Metabolism

Question 17

what did the drug company do to protect its market share

Answer 17

• chiral switch
• Patent and sell drug as a racemic mixture
  
  • Requires that both enantiomers are safe
  • Only one enantiomer needs to be active
• Just before patent expires patent single enantiomer form
  
  • Often done on manufacturing process
• FDA considers single enantiomer as a new formulation
  
  • easy way to get FDA approval

Question 18

how did the company convince doctors and show that their new drug was advantageous to the FDA

Answer 18

• there are two isomers for the drug R or S
• The R isomer is metabolized slightly faster than the S isomer
  
  • Liver converts some of the R form into the S form
• The S isomer lasts a little longer in the body
  
  • In principle, require less frequent dosing
  • S will last quicker than the racemic form

Question 19

what is the name of the new drug and which isomer does it contain

Answer 19

nexium, s isomer

Question 20

what advantage does nexium have over prilosec

Answer 20

none. the company jsut needed to save their butt.
but fine:
- The R isomer is metabolized slightly faster than the S isomer
- Liver converts some of the R form into the S form
- The S isomer lasts a little longer in the body
- In principle, require less frequent dosing
- in principle is the main thing. they were too vague in their explanation and this new drug is not remarkable enough.