44- proton pump Flashcards
what is the proton pump
enzyme + Pore structure that spans the membranes of parietal cells. Pore structure that spans the membranes of parietal cells
what are parietal cells
are the cells lining the stomach that produce acid
what is the difference between H2 and proton pump inhibitor
what is the difference between H2 and proton pump inhibitor
- 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
how is proton pump an ATPase, what does the hydrolysis of ATP contribute to the cell
- 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
what does the drug target in the proton pump
Inhibit ATP hydrolysis to inhibit the enzyme
outline the discovery of the proton pump enzyme
- Enzyme characterized
- Inhibition mechanism elucidated
- Lead compound identified by HTS
how does the lead compound turn into its active form
under pH 2 it will undergo a chain of reactions turning it into a permanent cation
what is the inhibition mechanism for the drug
look at notes
how does the bioavailability of the drug give selective amplification
- 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
- Only protonated below pH 2
- 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
how does the drug become trapped in the stomach
- 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
what drug form is required for selective delivery
- 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
what are the requirements for the pill
- 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)
what special feature do the pills have
- 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
what is omeprazole
- delayed-release drug (acid reducer)
- prilosec is the brand name
how did the drug company for prilosec use a market share extension
- 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
in which three ways do enantiomers act differently in the body
- Efficacy
- Side effects
- Metabolism
what did the drug company do to protect its market share
- 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
how did the company convince doctors and show that their new drug was advantageous to the FDA
- 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
what is the name of the new drug and which isomer does it contain
nexium, s isomer
what advantage does nexium have over prilosec
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.
