peptic ulcers

Question 1

rational drug design - James Black

Answer 1

involves understanding the natural ligands that might regulate a receptor cell surface receptor and then changing the structure of those molecules to either increase the potency or Effectiveness or to block the receptor.
- . These are known as antagonists.
- you don’t really need to know what the receptor is. You don’t need to know the molecular identity of the receptor. You just need to know what the structure of the ligand is that induces that response
- and then you modify the structure of the chemistry of that to try and get better drugs, better ligands that will either block the receptor or activate the receptor with greater potency.
- And that strategy is used multiple times during this discovery process and he’s used it in a similar way for the discovery of drugs used to treat peptic ulcers

Question 2

marshalls discovery

Answer 2

discovered that peptic ulcers were actually caused by a bacterial infection helicobacter bacteria
- and this completely changed the whole sort of field of peptic ulcers and it took many years for that Discovery to kind of reach a consensus and he was often regarded as a bit of a quack
- over the years his theory gained prominence

Question 3

the stomach

Answer 3

• You’ve got the fundus the Corpus and the Antrim
• and then you’ve got the pylorus which allows all the contents of the stomach to go into the duodenum
  -and there are different cells located in these different regions of the stomach

Question 4

major cells types of the stomach that are involved in gastric secretion

Answer 4

• parietal cells - the secrete hydrochloric acid. They also secrete intrinsic factor.
• The chief cells secrete pepsinogen. This is a digestive enzyme that breaks down proteins.
• You’ve also got G cells which are an Endocrine cells that secrete gastrin and gastrin has an important role in control of gastric acid secretion.
• enterochromaffin cells and they secrete histamine and that has an important role in the control of acid secretion
  and all of these are effectively some of the targets for some of the drugs that were
  developed for the treatment of peptic ulcer

Question 5

control of gastric secretion - gastrin

Answer 5

the cells that secrete acid are the parietal cells.
○ this is controlled by gastrin that is secreted from the G cells within the stomach and that gastrin is a hormone that activates a receptor that is very similar to cholecystokinin receptor.
○ It’s a slightly different receptor and those tend to be expressed on the pancreatic acinar cells that secrete digestive enzymes.

Question 6

control of gastric secretion - nerve cells

Answer 6

• You’ve also got nerve cells that secrete acetyl choline, which is the major neurotransmitter that controls acid secretion.
  ○ So for example, during the sort of smell and and sight of food you start your stomach starts rumbling, and that’s mainly caused by your nervous system, which is the parasympathetic nervous system which controls the secretion of gastric acid
  ○ And so acetyl choline activates the muscarinic receptor on the parietal cells and that’s important for secretion of acid,

Question 7

control of gastric secretion - enterochromaffin cells

Answer 7

• So even though there are gastrin receptors on the parietal cells and muscarinic receptors on the parietal cells, The major mechanism for controlling acid secretion comes from the secretion of histamine from the enterochromaffin cells.
• And it’s the histamine That’s the major driving force and the major control mechanism for acid secretion
  . If you remove that histamine, then the acid secretion is reduced to a minimum and a minimum control by gastrin and acetylcholine

Question 8

activation of tubular vesicles

Answer 8

you’ve got these tubular vesicles that have a very high surface area, but then once activated by histamine or acetyl choline or gastrin these all activate these various G protein-coupled receptors that increase intracellular calcium.
- So they activate G proteins that couple to G Alpha q that then activates phospholipase C and the phospholipase C converts phosphoinositol bisphosphate into IP 3 and diacylglycerol
- and the ip3 activates calcium release from the endoplasmic reticulum.
- And you get this huge increase in calcium and that calcium activates the secretion of of acid
- and likewise cAMP coupled to G alpha s mediated G proteins is also involved in the control of acid secretion

and once activated these tubular vesicles become these canaliculi and these have a huge surface area now and once they are activated there is a six to ten fold increase in the number of these proton pumps that are on the apical surface. and this increases massively increases the amount of acid that gets secreted.

Question 9

ulcer

Answer 9

acid/ enzyme damage to stomach or intestinal wall
- 10% europeans and north americans affected
- complications: GI bleeding, perforation

if theres a perforation acid can leak out, you can have a major bleed and if that perforation goes through the entire duodenal wall then all of that acid will ne leaking out into the peritoneum

• until1970s required surgery

Question 10

H2 antagonists

Answer 10

• cimetidine was the first line H2 antagonist for the treatment of ulcers and the structure is kind of similar to histamine
• identified by design e.g. compounds with structural motifs similar to histamine
• And this provided a classification of the histamine receptors because up until that time they didn’t really know what the drug targets were.
  The control of acid secretion is very specifically H2 receptors and the H2 receptors are only expressed in the stomach. So they have a very specific role and therefore drugs that act at these are unlikely to effect H1 receptors and control allergies,

Question 11

how do H2 antagonists work

Answer 11

they work in humans because histamine is the major mechanism for controlling acid secretion
- the major driving force for controlling acid secretion is histamine.
- And the activation of H2 receptors, so blocking that with an antagonist, is a very effective way at controlling acid secretion.

Question 12

H2 receptor antagonist drugs

Answer 12

• cimetidine
• ramatidine
• market huge = success for UK pharma in the 70s and 80s
• H2 antagonists still used = OTC indigestion relief and in pain relief often co-administered with NSAIDs
• late 1980s expiration of patent for H2 antagonists = opened market for new drugs

Question 13

potential anti ulcer drug targets

Answer 13

• muscarinic ACh = side effects
• gastrin receptors = no success
  -ion channels and transporters
  - K+ channels
  - Cl- channels
  
  • H+-K+ ATPase

Question 14

proton pump inhibitors

Answer 14

so there was a huge drive to develop proton pump inhibitors and these were discovered
in the early 70s,
- an accidental Discovery because there was this search for gastrin receptor antagonists and there was a class of drug known as the thioamide which affected acid secretion
- and these were developed because they were thought to be gastrin antagonist, but further scrutiny of the mechanism realized that these were not affecting gastrin receptors, but we’re doing something else but they were very effective at reducing acid secretion
- and by 1977. it was disocvered That this proton pump was responsible for the effects of these thioamides
- meant that you could now use that as a structural backbone to develop more specific drugs that were inhibiting the proton pump and nothing else

Question 15

omeprazole - 1st generation proton pump inhibitor

Answer 15

• lipid soluble (so gets absorbed in GI tract) , weak base - enters and accumulates in acid spaces (canaliculi of parietal cell)
• activated in acid (so its a prodrug) - chemically altered by H+ to an active sulphenamide form
• IC50 = 50 nM (means its very potent)
• forms irreversible S-S bond with H+ - K+ ATPase

Question 16

mechanism of omeprazole

Answer 16

• So you’ve got the lipid soluble Omeprazole that accumulates within acidic environments and then there is a chemical modification that activates it.
• And then once its active as this sulfenamide intermediate It’s highly reactive but it’s only going to be acting where there is an acidic environment.
• and so it binds covalently through this disulfide Bond and it’s kind of effectively inactivated that proton pump
  
  • and the only way that it would be reactivated is if it gets recycled.

Question 17

downside of omeprazole - broken down in acidic environment

Answer 17

• if you’re taking the drug orally its going to accumulate within the acidic environment where the stomach acid is but that’s not how it works. It has to be absorbed because once it’s in that acidic environment and it’s not been activated it will be degraded by the acid environment.
  
  • And so you actually have to enterically coat the Omeprazole so that it bypasses the acid degradation within stomach it then enters the duodenum
  • and once it’s in the duodenum that enteric coating drops off and then it gets absorbed because it’s lipid-soluble, freely diffuses across the epithelium of the duodenum into the blood

Question 18

when did patent for omeprazole expire

Answer 18

2001
that led to the second generation of proton pump inhibitors and the new drug esomeprazole,

Question 19

esomeprazole: Nexium

Answer 19

this was patented in 1993, but it took seven years for it to be approved as there was a lot of problems
- First of all omeprazole was a mixture of optical Isomers - It’s only one of those isomers
○ half of them are the r isomer and half of them are the S isomer but only the S Isomer is active in humans.
- all they did was they purified the S isomer and marketed that as Nexium and that managed to get through the course
- they managed to separate out the isomer and purify it and that meant that it was double the potency just because you’ve removed the most effective isomer
now whether that is a new discovery is highly debatable, but they managed to get it patented and then they managed to get it approved and this became the next big Blockbuster drug and made eight point three billion dollars a year as a new drug

Question 20

causes of ulcers

Answer 20

-bacterial infection helicobacter pylori
- non steroidal anti inflammatory drugs
- smoking
- zollinger Ellison syndrome
- anxiety/ stress

Question 21

helicobacter pylori

Answer 21

Barry Marshall discovered that there was this gram-negative bacteria that was responsible for the inflammation of the stomach lining
- and apparently 50% of the UK population are infected with this bacteria.

and the reason why it was so difficult to discover was because why would bacteria be in an environment with lots of acid
- and it turns out that these are resistant to the acid but the acid actually slows the growth of the bacteria which seems to be counter intuitive
- and so as soon as you take the gastric secretions and put it in a culture the bacteria don’t grow very fast.
- So it was very difficult - they just couldn’t really grow any bacteria. So that suggested that there wasn’t any bacteria in there

Barry Marshall actually ingested loads of these bacteria And became infected and got gastritis and that’s how we prove that it was working.

The other interesting point about this is that only 15% of those that are infected actually develop ulcers.

Question 22

helicobactor pylori infection

Answer 22

• bacteria able to tolerate low pH of the stomach
• metabolise urea = increased local pH with NH3 released
• penetrates mucus and lives attached to epithelial cells
• inflammation in the antrum impairs somatostain release = increased gastrin and so increased acid secretion

Question 23

negative feedback loop - control of H+ secretion

Answer 23

there’s this negative feedback loop where acid activates the endocrine Delta cells to secrete
somatostatin which switches off gastrin secretion which therefore switches off histamine secretion.
So this is a normal negative feedback loop that prevents too much acid from being secreted but then the bacteria cause the inflammation and impaired these Endocrine cells from secreting somatostatin and you lose that negative feedback loop and that increases histamine secretion and increases acid secretions.

Question 24

quadruple therapy - eraticate H.pylori = cure for ulcers

Answer 24

-2 antibiotics: clarythromycin; amoxycillin; metronidazole; tetracycline
- proton pump inhibitor
- bismuth compounds

Question 25

why PPI and Bismuth

Answer 25

• H.pylori tolerates acid pH but only grows quickly at pH 6-8
• antibiotics work best on dividing bacteria
• PPI raises ambient pH; Bi2+ slows furhter acidification of bacterial interior
• so PPI and Bi 2+ enhance antibiotic action

the idea is that both of these drugs actually allow the antibiotics to work more effectively on the growing bacteria. So it actually allows the bacteria to grow rapidly and then it allows the antibiotics to work