H2 Receptor Antagonists and PPIs

What is a peptic ulcer?

What causes it?

Risk factors that predispose someone to it?

What does one feel like?

- Localised erosion of the mucosal membrane (you will see white spots)- pain, irritation; caused by

exposed surface to stomach acid

- Causes: stress, alcohol, NSAIDs and H.pylori

- Potentiated by excess acid in the stomach - heartburn, indigestion, acid reflux

- Burning sensation - discomfort to excruciating pain, hole in abdomen,

mistaken as a heart attack

What is the mechanism for how gastric acid is secreted ?

- CO 2 and water combine (via carbonic anhydrase) to produce carbonate which

dissociates into bicarbonate and a proton – this proton is released via H-K-

ATPase pump

- Bicarbonate is actively excreted at the basal side of the cell and is exchanged

for chloride ions

- At the apical side of the cell, potassium ions go in and are exchanged for

protons which come out

- These chloride ions and protons make acid (in the chyme in the stomach lumen)- the H-K ATPase pump releases

the H+

- The HCl acid deactivates ingested bacteria and denatures ingested proteins

to allow for efficient protease reactions

What are the types of cells found in gastric glands in the walls of the stomach?

Several types of cells are found in the gastric glands: parietal, chief, mucus-

secreting, hormone-secreting cells (Gastrin) (some drugs target parietal cells)

What pump does the parietal cells have that is crucial in gastric secretion?

Parietal cells contain a H-K-ATPase pump which lets H+ ions out

How do transmembrane proteins in stomach cells secrete protons?

Via active transport using ATP

What is the concentration and pH of protons in the gastric juice?

can be as high as 0.15

mol/L, giving gastric juices pH <1

What is the concentration of protons within stomach cells ?

40 nmol/L

note: These cells are rich in mitochondria and consume high levels of energy

What are the sites for pharmaceutical manipulation to deal with the excessive acids?

- Antacids are alkaline substances which quickly neutralise acid in the stomach (short term relief as body keep making the acid)

- H2 antagonists reduce the production of histamine in the stomach

- Gastric PPIs inhibit enzymes stimulating acid secretion (therefore inhibit

proton release)

- Antimicrobial agents destroy bacteria which may cause ulcers (for acid being caused by bacteria)

DRUG PROFILE : ANTACIDS

Function

MOA

Examples

Actives

-Rapid pain relief

- Come in gums, lozenges, tablets, powders and liquids: short-term relief only

removing excess acid doesn’t solve underlying problem

- Effectiveness depends on their form and their ability to neutralise the acid

- Sodium carbonate, calcium carbonate, aluminium or magnesium salts

e.g. Gaviscon or Alka-Seltzer

Histamine chemical structure and pka's - what causes the interaction with the H2 receptor specifically?

- At physiological pH, histamine exists as

protonated at the primary amine—the H on the ring can either be in the tele

position or the pros position- this matters because in one way it interacts with

the receptor and doesn’t at the other position

- pKa changes based on side chain e.g., 5.94 on diagram

- About 80% of histamine mono cation (one charge) exists in aqueous solution that binds to

the receptor

- The tele tautomer (H on the N = tele) allows binding with the receptor but not in

the pros position

- Tautomerism is important for H2 interaction and not with H 1 interaction

Describe the conformation analysis of Histamine

- The trans conformer has less steric hindrance but the gauche conformer

is stabilised by an ion-dipole interaction because we have ion and aromatic

ring

- Both conforms exist in solution

- It is believed that both H1 and H2 receptors bind to the trans conformer- this is

based on the observation that alpha and beta methyl histamine are unable to

assume the trans conformation and are weak agonists at both the H1 and H2

receptors

Describe how we synthesised Histamine Analogues

-Aim is to block the H2 receptor! (As histamine usually binds to the H2 receptor to release gastric acid)

- The Guanidine analogue was synthesised and tested as an antagonist but

was found to be an agonist instead which stimulated acid secretion rather

than blocking

- Replace Guanidine with Thiourea = guanidine is really basic which picks up

a proton but thiourea is less basic

- Replacing C=N with C=S gives Thiourea = the pKa drops to 7.5 and this

compound acts as an antagonist

- But H in wrong position so now make Metiamide which has methyl

group which pushes electrons into the ring and the S has an inductive

effect on the N of the ring as it is more electronegative than C = Electron Withdrawing Group (EWG)

induction effect

- Metiamide 10x more active than Burimamide but had some toxicity due to

thiourea moiety - decrease in No. of WBC's = more susceptiple to infections ... we needed to still develop this analogue

- We tried replacing the Thiourea group of metiamide with Urea and Guanidine (which no longer showed agonist effect as this guanidine will be fully protonated) but neither was as effective as metiamide

Now what do we do? - Key thing is to look at pKa values

Memitiamide structure

Describe how we synthesised Histamine Analogues part 2. Cimetidine Development

- CN (triple bond) is EWG = gives pKa of 0

- To change the properties of a drug, look at

functional group and see what happens if

they are changed

- Want something less basic as possible

- Keep rest of molecule the same but add -CN bond = Cimetidine

- Nitro group, NO 2 , is also EWG

-Strong electron-withdrawing substituents, Cyano and Nitro group, make the guanidine group less basic and less ionized

Ranitidine and Famotidine Drug profile

Ranitidine:

• Furan derivative, an isostere of the imidazole with an electrons on the oxygen, with 50% bioavailability

• 4 -10 times more potent than cimetidine with fewer side effects

• Longer duration of action and weaker CYP inhibitor

Famotidine:

• Thiazole derivative • 40 - 60times more potent than Cimetidine and weak inhibitor of CYP

• 40 – 50% bioavailability due to incomplete absorption

Why did Ranitidine get withdrawn?

Impurity in the synthesis = toxicity

How were Proton pump inhibitors development

-Initially wanted to replace the Thioamide group in CMN 131 due to the Severe acute toxicity

-Replaced with a Benzimidazole of H 124/26

-Timoprazole is a metabolite of H 124/26 which has a Sulphoxide that can also be used as a PPI but it has a Side effect – enlargement of thyroid gland due to inhibition of iodine uptake in thyroid - not good

-Final one is Picoprazole with the addition of a methyly and a CH3OCO group on the aromatic ring, these had:

Potent anti-secretory properties over long periods No toxic side effects on thyroid No serious side effects

OMEPRAZOLE DRUG PROFILE: genral when and where in the body is it active and does it work

- Omeprazole is a weak base that accumulates in acidic areas. Substituents were added to its pyridine ring to adjust the pKa. his adjustment helps maximize accumulation in parietal cells (the cells that produce stomach acid), increasing its effectiveness

- Can be anywhere in body but will remain inert; it needs to be in the stomach

and needs the acid- when acid protonated the drug starts to change

- We initially thought that due to Lifelong toxicological studies at very high doses in rats revealed the endocrine

tumours in the stomach - we thought they were toxic

- This halted clinical studies until it was shown that tumours were due to very

high doses causing severe suppression

- Now we only use 20 mg dose

MOA of omeprazole

- Omeprazole is a prodrug and is protonated within the acidic canaliculi of the

parietal cells into the active form, a sulfenamide

- Accumulates in the stomach, once protonated the N Nu-attacks the C of C=N

= spiro intermediate

- Spiro intermediate opens up = break the bond between C-S and the S=O

picks up a proton as there

are many available forming Sulphenic acid

- The N will attack the S and

kick out OH but OH will pick

up a proton while leaving

- None of the intermediates

will inhibit acid secretion at

this point

- The ATPase pump has an -SH group which reacts with the S on (4) = now

ATPase pump will be stuck onto molecule (5) so cannot release acid = acid secretion is

inhibited

- This sulfenamide (the active compound) reacts with thiol groups in the

enzyme forming a disulphide link which inactivates the enzyme- this high

specificity of action is due to several factors

- N has to be protonated for mechanism to initiate (irreversible inhibition of the

ATPase pump)

What are the properties of Omeprazole - why does it have high specificity of action?

- Omeprazole is a weak base (pKa 4) - all PPI's are weak bases - therefore concentrates in acidic canaliculi

of the parietal cells

- The low pH causes the conversion into the active species close to the target

enzyme

- At higher pHs found in the body, omeprazole has good stability

- Commercial products are enteric coated to prevent gastric decomposition

Fun fact: Omeprazole has no optically active centre

What determines the rate of enzyme inhibition in PPI's

the rate of sulphenamide formation

What Two factors determine the extent to which PPI's accumulate in the canalicular lumen?

The pKa and the hydrophobicity of the PPIs

List some other PPI's and what are their properties - Why did Esomeprazole get licensed

-Pantoprazole

-Lansoprazole

-Rabeprazole

-Esomeprazole

Properties:

• The pH at which half of the maximum rate of activation occurs is 3.0 for Pantoprazole, 4.0 for Omeprazole and 5.0 for Lansoprazole.

• Differences in structure result in differences in pharmacokinetics, however, differences in oral bioavailability are not clinically important.

• All the PPIs are chiral because of the Sulphur, both isomers are converted into the nonchiral active species at the same rate.

Omeprazole vs Esomeprazole:

• In vivo, the S-omeprazole (esomeprazole) produced higher plasma concentrations because it undergoes less metabolism by CYP 2C19 and thus produces 70% higher AUC than Omeprazole

-Esomeprazole is the chiral compound of omeprazole (Shown on diagram)