1- pharmacology of gastric secretion

Question 1

what cells are in a gastric crypt?

Answer 1

• towards top is mucus cells that secrete mucus + bicarbonate = acting as protective layer
• towards bottom end there is parietal cells, enterochromaffin, G cells, D cells and chief cells

Question 2

what do parietal cells secrete?

Answer 2

hydrochloric acid (they’re found towards bottom of gastric crypt)

Question 3

what do enterochromaffin cells secrete?

Answer 3

histamine (they’re found towards bottom of gastric crypt)

Question 4

what do G cells secrete?

Answer 4

gastrin
(they’re found towards bottom of gastric crypt)

Question 5

what do D cells secrete?

Answer 5

somatostatin
(they’re found towards bottom of gastric crypt)

Question 6

what do chief cells secrete?

Answer 6

pepsinogen
(they’re found towards bottom of gastric crypt)

Question 7

what is paracrine and autocrine signalling mechanisms?

Answer 7

paracrine = adjacent cells influence through hormonal action to cells close by
autocrine = cells self regulate through hormonal action

= they are 2 predominant self mechanisms that influence secretion of HCl, bicarbonate, mucous

Question 8

what are the very different pH environments in gastric crypt?

Answer 8

• lower of gastric crypt + mucous layer = low pH (due to secretion of HCl into main gastric environment which has high HCl conc)
• with mucous layer = higher pH -presence of bicarbonate which forms protective barrier for cells of gastric crypt →if didn’t have then HCl could damage the cells

Question 9

how is HCl secreted from gastric parietal cells?

Answer 9

• the chloride/bicarbonate exchanger brings Cl- into cell from blood and gives HCO3- out
• the Cl- is pumped out into gastric lumen through chloride potassium symporter which pumps both Cl- and K+ simultaneously
• the K+ is bought into parietal cells from lumen in H+/K+ ATPase proton pump, the H+ is taken out from cell into lumen
• the bicarbonate is made from combined CO2, H2O and carbonic anhydrase, 1 H+ is then given off which goes to ATPase proton pump

Question 10

what does chloride/bicarbonate exchanger do in HCl secretion?

Answer 10

it transports chloride anions into parietal cell as well as bicarbonate transported out into blood plasma

Question 11

what does chloride potassium symporter do in HCl secretion?

Answer 11

transports potassium cations out at same time as chloride anions = at into gastric lumen

Question 12

what is the action of histamine when released from enterochromaffin-like cells?

Answer 12

1. histamine binds to histamine H2 receptors that activate adenylate cyclase that give rise to cAMP
2. cAMP eventually downstream positively modulates proton pump system = increases number of proton pumps so modulate secretion of HCl (gastric acid) from the parietal cells through paracrine system = leads to more gastric acid

Question 13

what is action of acetylcholine on parietal cells?

Answer 13

1. with parasympathetic response, acetylcholine is released and that will bind to muscarinic acetylcholine receptors on blood plasma side of parietal cells
2. this activates PLC which eventually increases intracellular calcium and eventually phosphorylates proton pumps so increases number of proton pumps so increases gastric secretion

Question 14

what is action of gastrin when released in gastric cells?

Answer 14

1. secretion of gastrin from G cells (paracrine system)
2. gastrin binds to CCK2 receptors which will stimulate PLC and (same as AChon parietal cells) increases intracellular calcium and then downstream signals eventually lead to increase in number of proton pumps = increase in gastric acid secretion

Question 15

what is action of somatostatin when released in gastric cells?

Answer 15

2 different mechanisms:
1. somatostatin release from D cells
2. binds to somatostatin type 2 receptor on parietal cells and inhibits adenylyl cyclase (Gi receptor) so reduces cAMP
3. leads to reduced proton pump activity so decreases HCl

1. somatostatin binds to somatostatin type 2 receptor on enterochromaffin cells
2. decreased production in histamine release = less to bind to histamine H2 receptors so more decrease on gastric acid secretion

Question 16

what are antacids?

Answer 16

drugs that work by buffering gastric acid e.g. gaviscon or peptac are examples of sodium alginate buffering systems (salt based compounds neutralise gastric acids)

Question 17

what is purpose of NSAID in gastric cells?

Answer 17

non steroidal anti-inflammatory drugs = they disrupt production of of prostaglandins by inhibiting COX1

Question 18

what is result of reduced prostaglandins in gastric crypt due to NSAIDs?

Answer 18

reduction in prostaglandins = histamine secretion from enterochromaffin like cells which promotes HCl secretion from parietal cells
= this is a side effect of NSAID

Question 19

what is misoprostol? when is it indicated and what are side effects?

Answer 19

= analogue (has similar chemimcal properties) of prostaglandin E1

• indicated for prophylaxis of NSAID induced peptic ulcer
• side effects = abdominal pain, diarrhoea

*induces labour so not for pregnancy!

Question 20

what are examples of proton pump inhibitors?

Answer 20

= omeprazole, lansoprazole, pantoprazole

Question 21

what is mechanism of proton pump inhibitor?

Answer 21

1. covalent interaction with proton pump that inactivates it (the pump that takes H+ out while bringing K+ in)
2. reduces gastric acid secretion

indicated for gastric acid ulceration (effective for NSAID associated gastric acid ulceration), gastric acid reflux syndrome

Question 22

what are side effects of proton pump inhibitors?

Answer 22

= increase systemic pH (low pH is defence against infection so elevating pH could reduce natural defence against infection in GI tract)

Question 23

what are examples of histamine receptor antagonists? and when would you prescribe?

Answer 23

famotidine, nizatidine and ranitidine

• indicated for gastric acid secretion, gastric acid ulceration

Question 24

what is action of histamine receptor antagonist?

Answer 24

1. reversibly block histamine receptor (Histamine type 2 receptor = main one in gut)
2. prevent histamine binding so reduces gastric acid secretion

Question 25

what is result of H.pylori infection?

Answer 25

1. presence of bacteria (H.pylori) in mucous layer
2. they eventually destroy mucous producing cells
3. this then disrupts production of mucous and gastric crypt
4. once you have no mucous, depleted bicarbonate which leaves everything exposed to gastric acid to enter previously protected area of gastric crypt = damaged cells →peptic ulcer

Question 26

how would you treat a h.pylori infection?

Answer 26

= reduce gastric acid secretion (proton pump inhibitors most effective) and get H.pylori with antibiotics (clarithromycin + amoxicillin + metronidazole)