H2 Antagonists- Antiulcers and Proton Pump Inhibitors

What is a peptic ulcer?

A peptic ulcer is an break (erosion) in the lining of the stomach or duodenum that is due to acid and pepsin

Gastric Ulcer- In the stomach

Duodenal Ulcer- In the Duodenum

What are the main causes of Peptic Ulcers?

1) NSAIDs inhibit COX-1 which is responsible for making prostaglandins. Prostaglandins inhibit acid secretion from parietal cells and also increase mucosal protection. NSAIDs, in short, decrease Stomach Lining defense against Acid

2) H Pylori infection- damages the mucosa and increases acid secretion

3) Stress, alcohol, and diet

Explain the 3 Chemical Messengers for Acid Secretion and how Prostaglandins tie into this?

The parietal cells in our stomach excrete HCL (Hydrochloric acid). Their activity is regulated by three stimulators

1) Histamine- H2 Receptor on Parietal Cell

- Activates Adenylate Cyclase which increases the level

cAMP which activates the Proton Pump

- Prostaglandin acts on this process and decreases the activation the proton pump

2) Gastrin-CCK2 Receptor

3) Acetylcholine- M3 Receptor

Explain the discovery of H2 Antagonists

The Lead Molecule was Histamine. Based on Histamine, we discovered N-guanylhistamine

N-guanylhistamine activates the H2 Receptor but not in the same way that histamine does, thus it blocks histamine from binding to the receptor (Think of competitive inhibition)- It acts as a partial agonist

Explain the structure of N-guanylhistamine and how that helps it play as a partial agonist/weak antagonist

The Guanidine group of the molecule is key here. It allows it to bind to the receptor but not strongly activate it the way Histamine does. The structure is unique because it can bind to both regions of the receptor. Think of the receptor as having two regions. The agonist binding region and the antagonist binding region. Depending on where a ligand binds, determines how it behaves with the receptor. Histamine can only bond at the agonist binding region and thus strongly activates it. However, N-guanylhistamine can bind to both regions and can play both agonist and antagonist which allows it to behave like a partial agonist/weak antagonist

Explain the discovery of SFK 91581 and Burimamide

Replacing the Guanidine group with Neutral Thiourea gives us SFK 91581, a molecule that is a weak antagonist with no agonist activity. Further chain extension and addition of the N-methyl group gives us burimamide which is a 100 times more potent than N-guanylhistamine

Explain the development of metiamide

In burimamide, they decided to hone in on the Imidazole ring. First, they modified the pKa of it by adding in an electron withdrawing group like sulfur on the carbon chain. After that, they added in a methyl group at carbon 4 of the imidazole ring. That gives us the molecule Metiamide which is 10 times more active than burimamide . It showed promise, however, patients suffered from kidney damage due to it. So they went back to viewing the guanidine group.

Explain the further development of Guanidine.

In simple, they had to make the guanidine more non-basic which would make it more active. This meant they had to add Electron withdrawing groups like Nitro or cyano groups. They ended up discovering that the cyanoguanidine group was more potent. This is how we discovered Cimetidine (Tagamet) which was the first marketed H2 antagonist.

Explain Cimetidine

Cimetidine (Tagamet) causes side effects due to its imidazole ring. The ring affects CYP450 which affects how we take other medications like Warfarin or diazepam because CYP450 is crucial in metabolizing these drugs.

Explain Ranitidine (Zantac)

The imidazole ring was replaced with a furan ring and cyanoguanidine was replaced with nitroketeneaminal group

The dimethyl amino group plays as a cationic centre to have interactions with the receptor.

10 times more potent than cimetidine and is a weak inhibitor of CYP450 mixed functions

However, it was recalled due to NDMA contamination

Explain Famotidine (Ausfam)

Famotidine is 30 times more active than Cimetidine

The imidazole ring in cimetidine has been replaced by Thiazole and the side chain contains sulphonylamidine

Explain Nizatidine (Nizac)

Based on Ranitidine, Furan ring is replaced with thiazole ring.

Explain Omeprazole (Losec)

Omeprazole has Benzimidazole, Pyridine Ring and a Methylsulfinyl linker

Explain the effects of pyridine substituents on Omeprazole

Omeprazole is a prodrug, it only becomes active in acidic pH once it has been protonated. It gets protonated at the pyridine ring. The positioning of the substituents relative to the nitrogen plays a role in how easily the ring gets protonated and how stable the prodrug is before getting activated. It is preferable for Methoxy to be in the para position because they increase electron density on the pyridine nitrogen which makes it more basic and this easily more protonated in acidic conditions. The methyl groups being meta ensures that the drug doesn't get activated too early.

Proton Pump Inhibitors

Omeprazole-Losec

Pantoprazole-Somac

Lansoprazole- Zoton

Rabeprazole- Pariet

Explain how Proton Pump Inhibition works

Our target with Proton Pump inhinitors is H/K ATPase. It is a transmembrane protein with cysteine residues that are accessible to drugs. Cysteine has a Thiol (-SH) group which is highly nucleophilic. PPIs are prodrugs that become reactive sulfenamides after activation. This reacts with the thiol group. PPIs attach covalently to Cys which is an irreversible inactivation of the protein and will inhibit it until more pumps are made (That's why they are long acting).

Explain the 3 forms of PPI structure

PPIs have two basic nitrogens which can be protonated at acidic pH:

1) Pyridine Nitrogen

2) Benzimidazole Nitrogen

These means that three cationic forms are possible, one where the pyridine is cationic, one where the benzimidazole is cationic, and one where both are cationic. The most important one for Proton Pump Inhibition is the one where only Benzimidazole is protonated.

Explain Omeprazole Single Enantiomer and Lansoprazole Single Enantiomer

The S-Enantiomer (Based on chiral Sulfur) in Esomperazole (Nexium)

The S-Enantiomer of Lansoprazole is Dexlansoprazole

Explain Enteric Coated and Immediate Release PPIs

PPIs are destroyed by stomach acid. In our stomach, uncoated omeprazole would degrade before reaching our parietal cells. This is why we add enteric coating. It is able to resist degradation and give the drug enough protection to reach our small intestine where it can be absorbed into our circulation to reach our parietal cells. Essentially allows more drug to reach our parietal cells by delaying activation all the way until the end of the sequence.

The downside of Enteric Coated PPIs is that we have to take them 30-60 minutes before meals in order for them to work efficiently. Basically it takes a while for them to work

Immediate Release tablets use a buffering agent like Sodium Bicarbonate to temporarily raise the pH of the stomach which allows it to pass through our stomach faster and get absorbed faster

Explain Misoprostol

Misoprostol (Cytotec) is an analogue of Prostaglandin and is used to preserve the integrity of our stomach lining. Used to prevent NSAID induced gastric ulcers. It is also used to induce abortion

Pharmacological Treatment of GORD

1) H2 Blockers

2) Proton Pump Inhibitors

3) Antacids

Combination Therapy in H Pylori Infections

1) PPI Twice Daily

Clarithromycin 500 mg twice daily

Amoxicillin 1g twice daily

Total: 14 days

If amoxicillin is unsuitable, use metronidazole 400mg twice daily

Therapy for NSAID Induced Peptic Ulcer

1. Stop the NSAID (except for low dose aspirin)

2. Substitute Paracetamol and non drug treatment

3. Treat with a PPI for at least 8 weeks