H2RAs and PPIs

Question 1

What modifications can be made to histamine to develop H2RAs?

Answer 1

Modify the amine
Modify the alkyl side chains
Alter the substituents on the imidazole ring

Question 2

How do we initially try to get antagonism at the H2RA?

Answer 2

1. conformational blocking adding methyl group to give steric clash for selectivity at the H2 over H1
2. Altering the terminal NH2 - weak antagonist

Question 3

How to form burimamide, what does it give and what are the drawbacks?

Answer 3

Replace guanidine group with thiourea group
Extend carbon chain - full antagonist
But it has poor bioavailability/activity and the thiourea group toxic

Question 4

What is thiaburimamide? How do we form thiaburimamide from burimamide?

Answer 4

Enhancing the H2 antagonism.

Added a heteroatom in the middle of the chain (S) isostere of methylene group. Still has toxicity

Question 5

How do we optimise antagonistic activity ?

Answer 5

Stabilise the optimal tautomer for H2RA - by adding EDG at C4 and EWG at C5 on the imidazole ring
This gives metiamide which is a full H2RA, bioavailable, but still toxicity

Question 6

How do we het cimetidine from metiamide ?

Answer 6

Replace the thiourea group removes toxicity and produces cimetidine.
- Full antagonist, bioavailable, low toxicity, renally excreted, half life 2hours.

Question 7

What are the disadvantages to cimetidine/

Answer 7

1. inhibits CYP450 enzymes in the liver which metabolise many drugs, thus can interfere with Cp levels of other drugs in body esp warfarin, theophylline, diazepam.
2. CNS effects - can cross BBB and cause drowsiness, confusion, anxiety

Question 8

What structural features can be changed on cimetidine to ensure reduced CNS effects and reduced inhibition of CYP450?

Answer 8

Replace imidazole ring with heterocyclic rings e.g Furan ring - this produces ranitidine.

Question 9

What are the advantages of Ranitine over cimetidine?

Answer 9

Less lipid soluble than cimetidine- cannot pass BBB as well and produce CNS effects.

• Longer duration of action and 10x more active
• Only a weak inhibitor of CYP450 so less toxic metabolites

Question 10

What is the MoA of PPIS?

Answer 10

Irreversibly inhibit the H+/K+ ATPase enzyme complex - the proton pump. More superior than H2RA

Question 11

What is structure of PPIs

Answer 11

Pyridyl methylsulfinyl benzamidazole skeleton

Question 12

Define pro drug

Answer 12

Molecule inactive in itself but converted to the active drug in the body, by an enzymatic reaction or change in pH of the environment.

Question 13

What are the advantages of using Pro drugs over active?

Answer 13

• only work at the target site of action so fewer systemic s/e
• Give drug in much higher dose as concentrated only at the site needed - high activity there
• Often more stable as dont have reactive FGs like active

Question 14

How do PPIs act as pro drugs?

Answer 14

1. Drug taken in inactive form - into blood plasma pH 7.4
2. Get unionised (weak bases), unionised and lipophilic means it can pass the PM of parietal cell and enter
3. PPI is in very acidic conditions - canaliculi pH 1/2 so it gets ionised - protonated.
4. Ionised drug too polar to cross back out of membrane which results in 1000x fold accumulation in the canaliculi where inteded to act
5. Protonation also triggers an acid catalysed conversion of inactive –> active
6. Activated PPI forms a covalent disulfide bond with the proton pump - irreversible inhibition, long duration

Question 15

when are PPIs most active?

Answer 15

When the proton pump is actively secreting HCl because acid conditions needed to activate them - little activity when cells are in resting state

Question 16

Advantages of PPIs in general?

Answer 16

• the target enzyme H+/K+ ATPase is only present in parietal cells - selective
• Canaliculi only place in body to have such a low pH to activate it
• Drug only activated at target site due to protonation & cant return out of the cell to circulation
• Activated close to target and reacts rapidly
• Inactive at neutral / plasma pH less systemic S/E

Question 17

What are the advantages of PPIs over H2RAs?

Answer 17

1. Targeting the PP - end part. H2RAs only target the Histamine R but there are other receptors that can stimulate HCl release in body e.g gastrin/ACh so even if inhibit histamine it doesnt stop the others. Whereas inhibiting the PP is the final stages of HCl release - it prevents H+ release regardless of the mechanisms involved
2. Inhibition of the enzyme requires pyridine ring within PPI to be activated via protonation. Protonation more favourable if OMe group is para to pyridine N - binds irreversibly once activated and blocks pump completely.

Question 18

Explain the concept of chiral switching in relation to Omeprazole

Answer 18

Chiraal switching - replacing a racemic drug with single enantiomer. Couldnt have known before & has benefits.
e.g Changed to the S enantiomer - Esomeprazole as it can be given at higher doses thus better activity (chiral centre on the S)