Gastrointestinal / Liver

Question 1

Describe the control of gastric emptying

Answer 1

Local, neural, hormonal

Local:
- Gastric distension trigger myenteric and gastric reflexes
- feedback via AcH release increases GE
- duodenal distension inhibits to allow passage of duodenal contents
- properties of food can contribute: Solids have linear reduction (half life 1-2 hours), liquids have exponential, half life 20-30 min

Autonomic
- PSNS: CNX/vagal, increase GE (Ach)
- SNS: reduce GE

Hormonal:
- Stimulatory:
— Gastrin (gastric distension, release for G cells in stomach, via GPCR)

Inhibitory:
- duodenal chemo and osmoreceptors respond to presence of contents in chyme (food) to slow GE
- carbohydrate/glucose –> release of Gastroinhibitory peptide (GIP)
- protein/amino acids –> cholecystokinin (CCK), + GIP +Secretin (from stomach)
- Fat: CCK, GIP, Secretin
- Acid: secretin. Gastric cells also secrete somatostatin.

speed of emptying: carb>protein>fat

Question 2

What are the functions of gastric secretion

Answer 2

Gastric secretion is ~2L/day, plays role in digestion of food and mucosal protection

Parietal cell:
- HCl secretion: drops pH, allowing for ideal acidic conditions for proteolysis as well as bacterial protection. Facilitates iron absorption and activation of pepsin. inhibits gastrin secretion.
- intrinsic factor: binds to B12 and allows its absorption

Chief cell:
- pepsinogen: cleaved to pepsin by Hcl. is a pro-enzyme to digest protein

Mucous cell: alkaline mucous lubricates and protects lining of stomach from auto digestion
bicarbonate released to reduce activity of HCl.

G-cell: secretes gastrin which directly and indirectly activates parietal cells to secrete HCl (via histamine)
- increase motility, pancreatic secretion and gall bladder contraction

Enterochromaffin: secrete histamine to stimulate parietal cells

D-cells: somatostatin: antagonises stimulatory effect of histamine of parietal cells.

Question 3

How is HCL secreted by the stomach and controlled

Answer 3

HCl is secreted by the parietal and plays a large role in digestion by creating ideal pH for activation of pepsinogen to pepsin and subsequent proteolysis. bactericidal environment. Fe absorption.

See Diagram:

Mechanism: upon stimulation K+/H+ exchange pump change from being vesicles to then fusing with the membrane.
- h20 + CO2 –> H2CO2 –> H+ + HCO3- via carbonic anhydrase
- these exchange H+ out of the cell
- Cl then leaves the cell through ion channel. via electrical current
- water also follows osmotically
- Na/K/ATPase maintains intracellular K+ concentrations
- Cl/HCo3- allows Cl to enter cell and HCo3- to leave –> create alkaline tide (alkaline blood in venous circulation)

Control:
- this is regulated by Histamine, AcH (vagal/PSNS) and gremlin
- grelin indirectly causes histamine release from enterchromaffin cells

Cephalic phase: this about food - vagal stimulation, AChR –> grelin + histamine
Gastric phase: distension triggers AChR –> grelin –> histamine
- gastric contents also stimulates release
Intestinal phase (inhibitory):
- stretch of duodenum causes secretin release
- low pH and increasing fats can cause feedback to reduce gastric secretion via release of secretin, GIP and somatostatin

Question 4

How do antacids work

Answer 4

There are particulate antacids (ie ALOH-, Mg(OH)2 and CaCo3, Mylanta/gaviscon/quickeze etc) and non-particulate antacids (Na citrate)

Particulate: insoluble alkaline that reacts with acid to form an insoluble neural salt. Quick acting and more efficient than Na Citrate but damages the lung causing pneumonitis if aspirated.
Non-particulate: alkaline substance that reacts with acid to form neutral soluble salt.

reduction in acidity also causes less ctivation of pepsin (pH>5), reduced motility and increase LOS tone.

Question 5

How do Histamine 2 receptor antagonist work

Answer 5

H2RB (ranitidine, cimetidine, nizatedine)

MoA: inhibit Histamine 2 receptor GsPCR) in parietal cells. Less activation of cAMP, less H+ production, less H+/K/ATPase.

A: good oral (50%) Nizatedine 100%
D: 15% bound. 1.5L/kg. cross BBB
M: if orally absorbed: liver phase 1 CYP450
E: excreted in urine. half life 1.5-4h

Question 6

Tell me about PPI’s

Answer 6

PPI, commonly used for reduction if gastric volume and acidity. Pantoprazole, omeprazole, esomeprazole

MoA: directly irreversibly inhibit K+/H+/ATPase on canicular membrane of parietal cells. Most potent ion pH reduction, But takes longer to achieve effect than H2RB

A: good oral absorption 60-85%. only pantoprazole IV
D: distributed to parietal cells. peak [] in 2-4 hours, lasts >24 hours (ion trapping)
M: hepatic cyp450 to inactive metabolites
E: renal + bile 1/2 life 0.5-1.5 hours

Question 7

How do prostaglandin analogues and anti-muscarinics reduce gastric acid

Answer 7

PGE-1 (misoprostol)

prostaglandin stimulates GiPCR on parietal cells to inhibit cAMP and reduce H+/K+/ATPase
also acts on mucous secreting cells to increase secretion of alkaline mucous. (HCO3-)
can also cause uterine contraction/tone –> miscarriage

antimuscarinics: (glycol, atropine, pirenzipine)
- inhibit acetyl CoA stimulation of parietal cell as well as effect on gastrin secreting G-cells. inhibit GqPCR –> less IP3 –> DAG.
has anticholinergic SE’s.

Question 8

What are the areas that stimulate the Vomiting centre - what receptors do they have

Answer 8

CTZ (Chemoreceptor Trigger Zone)
- located on caudal end of 4th ventricle
- highly vascular - lacks a true BBB
- D2 and 5HT3 receptors

GIT via Vagus Nerve
- detects toxins and cerebral cortex distension, causes release of 5HT3
- vagal afferents via 5HT3 receptors stimulate CTZ and vomiting centre
- alos has NK-1 receptors

Vestibular system:
- located in bony labyrinth of temporal bone
- detects changes in position, motion sickness
- mACh receptors and histamine receptors –> CTZ

Cerebral cortex
- behavioural, anxiety, anticipatory, vomiting –> signals Vomiting centre
- Site of action for dexamethasone, propofol and midazolam