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YEAR 1 - Physiology and Pharmacology (Anton) > 9. Abdomen & Digestive System (TT) > Flashcards

9. Abdomen & Digestive System (TT) Flashcards

1
Q

What volume of secretions is released into the gastrointestinal tract per day?

A

7L

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2
Q

What are the main secretions that are secreted into the gastrointestinal tract?

A
  • Saliva
  • Gastric juice
  • Pancreatic juice
  • Bile
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3
Q

Describe the underlying similarities between pancreatic and salivary secretions.

A
  • Branching ductal arrangement, into which epithelial cell secretions are released
  • Secretions are composed of water, electrolytes and some digestive enzymes
  • Secretions aid digestion
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4
Q

Describe the structure of exocrine glands (e.g. salivary glands).

A
  • An acinus is up to 100 cells lining an intercalated duct
  • Lobules (secretory units) are made up of several acini
  • Intercalated ducts drain into intralobular ducts
  • Intralobular ducts drain into interlobular ducts
  • These drain into the main salivary or pancreatic duct
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5
Q

What is an acinus?

A
  • A small sac-like cavity in a gland, surrounded by secretory cells
  • In salivary and pancreatic glands, it is up to 100 cells surrounding an inercalated duct
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6
Q

What is the order of the tubes that form the structure of the salivary glands and exocrine pancreas?

A

Intercalated duct -> Intralobular ducts -> Interlobular ducts -> Main salivary or pancreatic duct

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7
Q

What is the basal rate of salivary secretion per minute and what does it rise to after stimulation?

A
  • 0.5ml/min
  • Rises to 5ml/min after stimulation
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8
Q

What is the average daily production of salivary secretions?

A

1.5L/day

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9
Q

What are the 3 types of salivary gland and what secretions does each produce?

A
  • Parotid
    • Produces watery (serous) secretions
    • 25% of total secretions
  • Submandibular
    • Produces both serous and mucous secretions
    • 70% of total secretions
  • Sublingual
    • Produces mucous secretion
    • 5% of total secretions
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10
Q

What type of secretions does the parotid salivary gland produce and what percentage of total secretions is this?

A

Serous (watery) secretion amounting to 25% of total.

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11
Q

What type of secretions does the submandibular salivary gland produce and what percentage of total secretions is this?

A

Both serous and mucous secretions, amounting to 70% of total.

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12
Q

What type of secretions does the sublingual salivary gland produce and what percentage of total secretions is this?

A

Produces mucous secretion, amounting to 5% of the total.

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13
Q

What is the difference in the composition of serous and mucous salivary secretions?

A
  • Serous secretions -> Containg the enzyme α-amylase
  • Mucous secretions -> Contain mucin
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14
Q

What does serous mean?

A

Watery

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15
Q

What is the function of the serous component of the saliva?

A
  • Moistening oral mucosa
  • Vehicle for enzymes
  • Lubrication (for speech)
  • Germicidal protection
  • Protective pellicle for teeth
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16
Q

What is the function of the mucous component of the saliva?

A
  • Lubrication
  • Diffusion barrier to nutrients, drugs, toxins
  • Binding bacteria, viruses, parasites
  • Protection against proteases
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17
Q

Describe the general mechanism of salivary gland secretion.

A

It is a two-stage process:

  • Primary secretion
    • Nearly isotonic solution (within similar levels of Na+, K+ and Cl- as the plasma)
    • It is the vehicle into which amylase is secreted
  • Secondary modification
    • Modification of the primary secretion by removal of sodium and replacement of it by potassium, as well as removal of chloride and replacement by bicarbonate
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18
Q

Where does primary secretion and secondary modification of the exocrine secretions (of the salivary glands and pancreas) occur?

A
  • Primary secretion -> Acinar cells
  • Secondary modification -> Duct cells
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19
Q

Describe the mechanism of primary secretion in the salivary glands.

A

Acinar cells essentially secrete isotonic NaCl:

  • Na+/K+-ATPase on the basolateral membrane creates a sodium gradient for the NKCC
  • Basolateral NKCC (Na+-K+-2Cl- co-transporter) accumulates Cl- ions inside the cell
  • Cl- ions diffuse across the apical membrane through channels
  • K+ diffuses out through basolateral channels
  • Na+ ions can also diffuse between cells into the lumen through tight junctions, along the electrical gradient established by Cl- movement
  • H2O follows by osmosis
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20
Q

Describe the mechanism of secondary modification in the salivary glands.

A

Duct cells modify primary secretion:

  • Na+ is absorbed on the apical membrane through ENaC (epithelial sodium channels) and Na+/H+ exchangers (NHE4) -> This is driven by the basolateral Na+/K+-ATPase
  • Cl- is reabsorbed on the apical membrane through Cl-/HCO3- exchangers (AE), then exits cell through Cl- channels on the basolateral membrane
  • HCO3<strong>-</strong> secreted in exchange for Cl- by the Cl-/HCO3- exchanger -> HCO3- is formed by CO2 and H2O in the cell
  • H+ from bicarbonate production is lost by the basolateral Na+/H+ exchanger (NHE1)
  • K<strong>+</strong> is accumulated in cells by the basolateral Na+/K+-ATPase, then lost to the lumen through a K+/H+-exchanger
  • H2O permeability is low
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21
Q

Compare the water permeability of the acinar cells and the intercalated duct cells of the salivary gland.

A
  • Acinar cells have a much higher water permeability, so water follows ions when they are secreted into the lumen (primary secretion)
  • Duct cells have a much lower water permeability, so when ions are secreted and reabsorbed, the water does not follow (secondary modification)
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22
Q

Describe the final composition of the salivary glands and how this compares to the primary secretion.

A
  • Primary secretion is very similar in ion composition to plasma
  • More ions exit than enter the duct, so the the final saliva is always hypotonic to plasma
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23
Q

What happens to the concentration of the salivary secretions as flow rate increases? Draw some graphs to illustrate this.

A

As flow rate increases, there is less time for secondary modification (in which more ions are reabsorbed than secreted), so the salivary secretions are not as hypotonic, but more isotonic.

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24
Q

What happens to the concentration of HCO3- in the salivary secretions as flow rate increases?

A

HCO3- is paradoxical:

  • As flow rate increases, you would expect HCO3- concentration to fall, since there is less time for secondary modification, in which HCO3- is usually secreted into the lumen
  • However, the agonists that stimulate the primary secretion (and therefore the flow rate), also stimulate HCO3- reabsorption, so the concentration of HCO3- is relatively constant
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25
Q

What happens to the pH of the salivary secretions as flow rate increases?

A
  • At rest, the pH is more acidic
  • When the flow rate increases, it becomes more basic, since HCO3- secretion is stimulated by agonists that stimulate primary secretion
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26
Q

What are some of the different protein components of salivary secretion that are secreted into the saliva by the acinar and duct cells?

A
  • Enzymes: α-amylase, Lingual lipase
  • Mucins
  • Kallikrein
  • Antimicrobial proteins: Lysozymes, lactoferrin, lactoperoxidase, proline-rich proteins, IgA
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27
Q

What are two examples of enzymes that are secreted into the salivary secretions?

A
  • α-amylase
  • Lingual lipase
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28
Q

What does α-amylase do?

A

Digests starch to maltose.

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29
Q

What does lingual lipase do?

A

Starts fat digestion

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30
Q

What type of molecule are mucins and what is their function?

A
  • Glycoproteins
  • Provide the barrier and binding functions of the mucous secretions
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31
Q

What is kallikrein and what is its function?

A
  • A protein that cleaves proteins to produce vasodilator peptides (e.g. bradykinin)
  • It is found in the mucous secretions of the salivary glands
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32
Q

What are some antimicrobial proteins found in the salivary secretions?

A
  • Lysozymes
  • Lactoferrin
  • Lactoperoxidase
  • Proline-rich proteins
  • IgA
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33
Q

In general, how is salivary secretion regulated?

A
  • By the autonomic nervous system, with the parasympathetic nervous system playing the most important role -> PNS causes the production of large volumes of saliva.
  • Substance P and VIP also cause increase production of saliva.
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34
Q

Describe how the acetylcholine, VIP and substance P nervous system regulate salivary secretion.

A

Parasympathetic nervous system causes increased rate of saliva production by stimulating primary secretion and inhibiting secondary secretion, which produces lots of dilute saliva:

  • ACh acts of M3 receptors that increase IP3 and therefore Ca2+ in the cytoplasm
  • Ca2+ stimulates protein kinases that phosphorylate channels on the apical and basolateral membranes
  • As a result, the permeability of the apical membrane to Cl- and the basolateral membrane to K+ is increased
  • Phosphorylation of the cytoskeletal elements induces exocytosis of vesicles containing proteins such as amylases

Substance P and VIP also increase intracellular Ca2+, so they also initiate secretion.

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35
Q

Describe how noradrenaline regulates salivary secretion.

A

Sympathetic stimulation increases salivary secretion, producing a viscous saliva:

  • Noradrenaline binding to α receptors increases IP3, which increases intracellular Ca2+
  • Ca2+ stimulates protein kinases that phosphorylate channels on the apical and basolateral membranes
  • As a result, the permeability of the apical membrane to Cl- and the basolateral membrane to K+ is increased
  • Phosphorylation of the cytoskeletal elements induces exocytosis of vesicles containing proteins such as amylases
  • Binding to β receptors raises cAMP, which activates protein kinase A and stimulates amylase secretion from vesicles
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36
Q

Compare the effects of sympathetic and parasympathetic stimulation of the salivary glands.

A
  • Both increase the secretion of saliva, which is an exception to the normal rule
  • Sympathetic stimulation results particularly in the increase of amylase secretion and vasoconstriction of blood vessels that supply the glands -> Leads to production a more serous, less dilute saliva.
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37
Q

Which is more important in controlling salivary secretion: sympathetic or parasympathetic control?

A

Parasympathetic

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38
Q

What triggers parasympathetic stimulation of salivary stimulation and what part of the brain is involved?

A

Salivary nucleus of the medulla:

  • Stimulated by: Conditioned reflexes, Smell, Taste, Pressure, Nausea
  • Inhibited by: Fatigue, Sleep, Dehydration, Fear
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39
Q

Which nerves are involved in the parasympathetic control of salivary secretion?

A

Cranial nerves IX (glossopharyngeal) and X (vagus)

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40
Q

Which sympathetic nerves are involved in the sympathetic control of the the salivary glands?

A

T1 to T3 nerve roots, which synapse at the superior cervical ganglion.

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41
Q

What percentage of the pancreas is exocrine?

A

90%

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42
Q

Where does the pancreatic duct go?

A

Unites with the common bile duct to drain into the duodenum.

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43
Q

How much pancreatic juice does the exocrine pancreas produce per day?

A

1.5L/day

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44
Q

What is the acidity of the pancreatic juice and why?

A

It is alkaline, so it can neutralise the acidity of the stomach acid.

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45
Q

How does pancreatic juice production compare to saliva production?

A

The primary secretion and secondary modification is similar to that in the salivary glands.

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46
Q

What does the water in the primary panreatic secretion do?

A

It hydrates digestive proteins released from the acinar cells.

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47
Q

Is there constitutive secretion at the exocrine pancreas?

A

Yes, but it can be increased up to 10-fold by receptor activation.

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48
Q

Describe the mechanism of primary secretion in the exocrine pancreas.

A

It is basically the same as in the salivary gland. Acinar cells essentially secrete isotonic NaCl:

  • Na+/K+-ATPase on the basolateral membrane creates a sodium gradient for the NKCC
  • Basolateral NKCC (Na+-K+-2Cl- co-transporter) accumulates Cl- ions inside the cell
  • Cl- ions diffuse across the apical membrane through channels
  • K+ diffuses out through basolateral channels
  • Na+ ions can also diffuse between cells into the lumen through tight junctions, along the electrical gradient established by Cl- movement
  • H2O follows by osmosis
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49
Q

What is the clinical relevance of the chloride transporter on the apical membrane of acinar cells in the exocrine pancreas?

A
  • It is the CFTR (cytsic fibrosis transmembrane conductance regulator)
  • It is mutated in cystic fibrosis, so secretion is mutated in these individuals
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50
Q

Describe the mechanism of secondary modification in the exocrine pancreas.

A

Duct cells modify primary secretion. The process is very similar to in the salivary glands:

  • Cl- is reabsorbed on the apical membrane through Cl-/HCO3- exchangers (AE), BUT then it exits the cell through Cl- channels on the APICAL membrane
  • HCO3- secreted in exchange for Cl- by the Cl-/HCO3- exchanger -> HCO3- is formed from CO2 and H2O in the cell
  • H+ from bicarbonate production is lost by the basolateral Na+/H+ exchanger (NHE1)
  • Na+ and K+ diffuse between cells down the electrochemical gradient
  • H2O permeability is low
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51
Q

Are all of the proteins secreted into the pancreatic juice active enzymes?

A

No, some of them are precursors that are later activated.

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52
Q

What is the name for precursor enzymes secreted by the exocrine pancreas?

A

Zymogens

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53
Q

Where are zymogens from the exocrine pancreas activated?

A

In the small intestine.

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54
Q

What are some of the protein components of exocrine pancreatic juice?

A
  • Proteases -> Trypsinogens, chymotrypsinogens, proproteases, procarboxypeptidases
  • Amylases
  • Lipases
  • Nucleases
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55
Q

What are some of the proteases produced by the pancreas?

A
  • Trypsinogens
  • Chymotrypsinogens
  • Proproteases
  • Procarboxypeptidases

These are all zymogens that will be activated in the small intestine lumen.

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56
Q

What is the purpose of zymogens?

A

It prevents autodigestion of the cells that secrete them.

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57
Q

How is premature activation of zymogens in the secretory cells prevented or controlled?

A
  • Presence of protease inhibitors in the secretory vesicles with the zymogens
  • Presence of nondigestive proteases to degrade active enzymes
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58
Q

What are the 3 phases of digestion that regulate pancreatic juice secretion? How does each control the pancreas?

A
  • Cephalic phase
    • Sight, smell and taste of food
    • Mediated by: ACh
  • Gastric phase
    • Distension of the stomach
    • Mediated by: ACh, Gastrin
  • Intestinal phase
    • Feedback phase, caused by the pH, distension, amino acids and fatty acids in the duodenum
    • Mediated by: ACh, Secretin, CCK (Cholecystokinin)
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59
Q

What is the cephalic phase of digestion and how does it stimulate secretion of pancreatic juice?

A
  • Sight, smell and taste of food
  • Mediated by: ACh
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60
Q

What is the gastric phase of digestion and how does it stimulate secretion of pancreatic juice?

A
  • Distension of the stomach
  • Mediated by: ACh, Gastrin
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61
Q

What is the intestinal phase of digestion and how does it stimulate secretion of pancreatic juice?

A
  • Feedback phase, caused by the pH, distension, amino acids and fatty acids in the duodenum
  • Mediated by: ACh, Secretin, CCK (Cholecystokinin)
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62
Q

ACh, Gastrin, Secretin and CCK all act to increase pancreatic juice secretion. What cells does each act on?

A
  • ACh and CCK -> On acinar and duct cells
  • Gastrin and secretin -> Only on duct cells
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63
Q

ACh mediates the production of pancreatic juice. Where is it released from and what triggers its release?

A
  • Released from vagal impulses
  • Triggered by:
    • Higher command (medulla)
    • Vagovagal reflex triggered by amino acids, fatty acids in duodenum (feedback loop from duodenum)
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64
Q

Gastrin mediates the production of pancreatic juice. Where is it released from and what triggers its release?

A
  • Released from G cells in the antrum of stomach
  • Triggered by:
    • Vagal stimulation of GRP-containing neurons in response to distension of stomach

GRP = Gastrin-releasing peptide

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65
Q

Secretin mediates the production of pancreatic juice. Where is it released from and what triggers its release?

A
  • Released from S cells in the duodenal epithelium
  • Triggered by:
    • H+ in duodenum
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66
Q

CCK (Chylecystokinin) mediates the production of pancreatic juice. Where is it released from and what triggers its release?

A
  • Released by I cells in the duodenal epithelium
  • Triggered by:
    • Amino acids and fatty acids in the duodenum
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67
Q

Describe the feedback that occurs to the exocrine pancreas in the intestinal phase of digestion.

A
  • Vagovagal reflex (ACh feedback)
  • S cells in duodenal epithelium cause secretin release -> Stimulated by H+ in duodenum
  • I cells in duodenal epithelium cause CCK release -> Stimulated by amino acids and fatty acids in the duodenum
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68
Q

Draw a summary of the different agonists that can act on the exocrine pancreatic cells and control secretion.

A
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69
Q

What important components of pancreatic juice does the spec mention?

A
  • Chloride
  • Bicarbonate

(Add flashcards on this?)

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70
Q

What are the functions of the stomach?

A
  • Secretes -> H+, pepsinogen, mucus, HCO3-, intrinsic factor (IF)
  • Mixes by muscular contraction
  • Releases humoral factors -> Gastrin, somatostatin, histamine
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71
Q

What is the purpose of the stomach secreting pepsinogen?

A

It is cleaved into pepsin in the stomach for the digestion of proteins.

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72
Q

What is the purpose of the stomach secreting mucus and bicarbonate ions?

A

They form a protective layer that prevents the stomach itself from being digested.

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73
Q

What is the purpose of the stomach secreting intrinsic factor (IF)?

A

It is used downstream in the small intestine to promote vitamin B12 absorption.

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74
Q

What does gastrin do in the stomach?

A

Stimulates gastric acid secretion.

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75
Q

What does somatostatin do in the stomach?

A

Inhibits acid secretion.

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76
Q

What does histamine do in the stomach?

A

Acts locally to stimulate gastrin acid secretion.

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77
Q

Compare gastrin, somatostatin and histamine, as well as their effects on the stomach.

A

Stimulate gastric secretion:

  • Gastrin (hormone)
  • Histamine (paracrine factor)

Inhibit gastric secretion:

  • Somatostatin (hormone)
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78
Q

What is the purpose of the acidic secretions in the stomach?

A
  • Antiseptic role
  • Initiate digestion by denaturing proteins
  • Promote truncation of pepsinogen to pepsin (and creates the right pH for its function)
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79
Q

Describe the structure of the stomach and what each part does.

A
  • Fundus -> Receives food
  • Body -> Secretes acid, pepsinogen, IF
  • Antrum -> Releases gastrin, somatostatin and holds food
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80
Q

What is the name for the glands in the body of the stomach?

A

Oxyntic glands

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81
Q

What controls the passage of food from the stomach to the small intestine?

A

Pyloric sphincter

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82
Q

Describe the structure of the gastric epithelium.

A

It is characterised by the gastric glands (a.k.a. oxyntic glands), which are invaginations of the epithelium that increase surface area.

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83
Q

Describe the different parts of a gastric gland.

A

Glands comprise pits, which open into a neck, which leads to a base. Below all this is a gastric muscalaris mucosa.

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84
Q

What are the different cells present in gastric glands, in order from the gastric lumen to the gastric lumen to the base of the pits?

A

In the pit:

  • Superficial epithelial cells

In the neck:

  • Mucous cells

In the neck and base:

  • Parietal (oxyntic) cells
  • Chief (peptic) cells

In the base:

  • Endocrine cells
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85
Q

Name the different types of cells in gastric glands. What are their different function?

A
  • Superficial epithelial cells -> Secrete mucus and HCO3-
  • Mucous cells -> Secrete mucus
  • Parietal (oxyntic) cells -> Secrete B12 and HCl
  • Chief (peptic) cells -> Secrete pepsinogen
  • Endocrine cells -> Secrete regulators such as gastrin, somatostatin (via the bloodstream)
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86
Q

Where in gastric glands are superficial epithelial cells found and what is their function?

A
  • At the top of the pit and in the surface lining of the stomach
  • Secrete mucus and HCO3-
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87
Q

Where in gastric glands are parietal (oxyntic) cells found and what is their function?

A
  • In the base and neck of the pit
  • Secrete HCl and intrinsic factor (for vitamin B12 absorption in the ileum)
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88
Q

Where in gastric glands are chief (peptic) cells found and what is their function?

A
  • In the base and neck of the pit
  • Secrete pepsinogen
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89
Q

Where in gastric glands are mucous cells found and what is their function?

A
  • In the neck of the pit
  • Secrete mucous
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90
Q

Where in gastric glands are endocrine cells found and what is their function?

A
  • At the base
  • Secrete regulators such as gastrin, somatostatin via the bloodstream -> These regulate gastrin acid secretion
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91
Q

Draw and explain a graph to show how the composition of gastric juice changes with secretion rate.

A
  • In an unstimulated stomach, the basal secretion originates from surface epithelial cells
    • This juice is rich in Na+ and Cl-
  • In the stimulated stomach, this is replaced by juice secreted by parietal cells
    • This juice is concentrated HCl

It is worth noting how much the Na+ concentration falls when the stomach is stimulated.

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92
Q

In an unstimulated stomach (i.e. low secretory rate), which cells produce most of the gastric juice and what is the resulting composition of the gastric juice?

A
  • Surface epithelial cells
  • The juice is high in Na+ and Cl+, as well as some bicarbonate to neutralise the stomach acid
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93
Q

In a stimulated stomach (i.e. high secretory rate), which cells produce most of the gastric juice and what is the resulting composition of the gastric juice?

A
  • Parietal (oxyntic) cells
  • The juice is high in concentrated HCl
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94
Q

What protein is responsible for secreting acid into the stomach lumen?

A

H+/K+-ATPase

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95
Q

Describe the structure of parietal (oxyntic) cells and how this relates to their function.

A
  • Secretory canaliculus (when stimulated)
    • This is an invagination of the apical membrane into the cell
    • Provide a larger surface area for secretion
  • Tubulovesicles (when unstimulated)
    • Found in the cytoplasm just under the apical membrane
    • Contain H+/K+-ATPases that are involved in secretion of HCl into the stomach

Note: The diagram is drawn with the basolateral membrane behind the page and the apical membrane in front of the page.

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96
Q

What cell type is this?

A

Parietal (oxyntic) cell

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97
Q

What is the role of the tubulovesicles in parietal cells?

A
  • They contain the H+/K+-ATPases
  • When the stomach is stimulated, the vesicles fuse with the membrane, inserting the ATPases into the membrane for acid secretion
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98
Q

What is the role of the canaliculi in parietal cells?

A

They increase the surface area of the apical membrane for acid secretion.

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99
Q

Draw a diagram to show the canaliculi and tubulovesicles in parietal cells of gastric glands in the stimulated and unstimulated state.

A
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100
Q

Why are the H+/K+-ATPases in the the tubulovesicles of parietal cells not active in the unstimulated state?

A
  • Vesicle is arranged so that ATPase is ‘inside out’
  • Even though there is ATP in the cytoplasm, the ATPase cannot funcition because the K+ cannot recycle back into the tubulovesicles
  • Low K+ availability within the vesicle ‘brakes’ the activity of the ATPase
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101
Q

How acidic can the pH of the stomach lumen be?

A

As low as pH 1.

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102
Q

Describe the cells from which acid is secreted in the stomach and what the mechanism of this gastric secretion is.

A
  • Cells: Parietal cells

The process is very similar to that in type A intercalated cells of the collecting duct:

  • Carbonic anhydrase catalyses hydration of CO2 in the cytosol to yield H+ and HCO3-
  • H+ ions are pumped into the lumen by the H+/K+-ATPase on the apical membrane in exchange for K+ -> The ATPases are inserted into the membrane from vesicles when the stomach is stimulated
  • K+ recycles out of the cell through apical K+ channels
  • HCO3- exits across basolateral membrane by a Cl-/HCO3- exchanger to the interstitial fluid, then the blood
  • Cl- ions diffuse through channels on the apical membrane to join H+ ions in the lumen
  • Water follows by osmosis

Net result: Secretion of HCl

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103
Q

What happens to the blood when acid is secreted into the stomach lumen?

A

It becomes more alkaline (‘alkaline tide’).

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104
Q

How can the H+/K+-ATPase in the stomach be inhibited and what is the result of this? [IMPORTANT]

A
  • Omeprazole (‘Losec’)
  • It prevents acid secretion into the lumen of the stomach
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105
Q

What is the name for the process by which transporters are inserted into the cell membrane from vesicles and then stored back in vesicles?

A

Membrane recycling

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106
Q

What is the endogenous regulation point for acid secretion in the stomach?

A

The movement of tubulovesicles containing H+/K+-ATPases into the membrane in parietal cells of gastric glands in the stomach.

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107
Q

What are the three methods of regulating gastric acid secretion that you need to know about?

A
  • Vagal stimulation (neurocrine)
  • Gastrin (endocrine)
  • Histamine (paracrine)
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108
Q

Describe how gastric acid secretion can be regulated endogenously by acetylcholine.

A
  • Acetylcholine from the vagus nerve binds to M3 muscarinic receptors
  • This triggers an IP3 cascade
  • PLC is activated, causing release of calcium from the ER
  • This calcium upregulates the fusion of tubulovesicles with the membrane, inserting H+/K+-ATPases into the membrane
  • This causes gastric acid secretion to be increased
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109
Q

From what cells is gastrin released from and what triggers this release?

A
  • G cells
  • Triggered by stimulation of GRP-containing nerves by vagus or protein digestion products in the stomach lumen
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110
Q

Describe how gastric acid secretion can be regulated endogenously by gastrin.

A
  • Gastrin is released from G cells in response to stimulation of GRP-containing nerves by vagus or protein digestion products in lumen.
  • Binds to CCKB receptors
  • This triggers an IP3 cascade
  • PLC is activated, causing release of calcium from the ER
  • This calcium upregulates the fusion of tubulovesicles with the membrane, inserting H+/K+-ATPases into the membrane
  • This causes gastric acid secretion to be increased
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111
Q

From what cells is histamine released in the stomach?

A

Enterochromaffin-like cells

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112
Q

Describe how gastric acid secretion can be regulated endogenously by histamine.

A
  • Gastrin is released from enterochromaffin-like cells
  • Binds to H2 receptors
  • This triggers an adenylate cyclase cascade
  • cAMP is increased, which stimulates PKA
  • PKA upregulates the fusion of tubulovesicles with the membrane, inserting H+/K+-ATPases into the membrane
  • This causes gastric acid secretion to be increased
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113
Q

How can histamine receptors be antagonised in the stomach and what is the result of this? [IMPORTANT]

A
  • Ranitidine (‘Zantac’)
  • It causes decreased gastric acid secretion
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114
Q

What is the common mediator theory and how did it arise?

A
  • There are 3 main ways of stimulating gastric acid secretion endogenously -> ACh, gastrin and histidine
  • Antagonists of histidine receptors (e.g. ranitidine) produce a much more singificant decrease in acid secretion than would be expected
  • This resulted in the common mediator theory:
    • Not only do ACh and gastrin act directly on the parietal cells that secrete the acid, but they also act on the enterochromaffin-like (ECL) cells that release histamine, and their binding stimulates the histidine release
    • This indirect pathway is responsible for a large fraction of gastric acid secretion stimulation
    • As a result, when histidine antagonists are used, they stop a large amount of gastric acid secretion
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115
Q

What cells release somatostatin?

A

D cells

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116
Q

What are the actions of somatostatin in the stomach?

A
  • Inhibits adenylyl cyclase and reduces gastric acid secretion from parietal cells of the gastric glands.
  • It essentially has the opposite action to histamine.
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117
Q

What controls somatostatin secretion (from D cells)?

A
  • Stimulated by: Low luminal pH
  • Inhibited by: ACh
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118
Q

What cells release secretin?

A

S cells in the duodenum

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119
Q

What controls the release of secretin and what are its actions in the stomach?

A
  • Release is stimulated by acid in the duodenum
  • Inhibits gastrin release
  • Stimulates somatostatin release

Together, this inhibits the gastric acid secretion.

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120
Q

What complication can Helicobacter pylori bacteria cause and how?

A
  • Can cause gastric ulcers
  • This occurs by the inhibition of somatostatin (which usually inhbits gastric acid secretion)
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121
Q

What are the 3 phases of digestion that regulate gastric acid secretion? How does each control the stomach?

A
  • Cephalic phase
    • Sight, smell and taste of food
    • Mediated by: ACh, GRP (gastrin-releasing peptide)
  • Gastric phase
    • Distension of the stomach -> Initiates vagovagal reflex
    • Protein digestion products -> Stimulate gastrin release from G cells
  • Intestinal phase
    • Presence of protein digestion products in the intestine
    • Stimulates gastrin release from G cells in the duodenum
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122
Q

How much does each phase of digestion contribute to total gastric secretion?

A
  • Cephalic = 30%
  • Gastric = 60%
  • Intestinal = 10%
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123
Q

How is pepsinogen activated?

A
  • Truncation of the N-terminal end to yield pepsin
  • This is a spontaneous event that occurs in acidic environments
  • Once active, a pepsin molecule can activate other pepsinogen molecules
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124
Q

What fraction of protein digestion is pepsin responsible for?

A

About 1/5th.

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125
Q

How does pepsinogen secretion occur?

A

It is secreted from secretory granules that fuse with the apical membrane of chief (peptic) cells.

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126
Q

What mediates the release of pepsinogen from chief (peptic) cells?

A

It is stimulated by:

  • ACh -> Binding to M3 receptors and triggering an IP3 cascade that leads to Ca2+ signalling
  • Gastrin + CCK -> Binding to CCKB receptors and triggering an IP3 cascade that leads to Ca2+ signalling
  • Secretin -> Binding to receptors that are coupled to adenylate cyclase that leads to cAMP signalling
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127
Q

What makes up the mucous that protects the stomach from acid?

A
  • Mucin (a glycoprotein secreted from mucous cells) that combines with water, salt and phospholipids
  • The result is a gel that is up to 200 micrometers thick
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128
Q

How does the mucous of the stomach protect from the acid in the lumen?

A

The gel is a barrier to H+ ion diffusion.

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129
Q

What is the purpose of surface epithelial cells of the gastric glands secreting bicarbonate?

A

HCO3- acts to neutralise any H+ ions that get into the protective mucous layer of the stomach.

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130
Q

How is mucin secretion from mucous cells of the gastric glands mediated?

A

Secretion is stimulated by ACh acting on M3 receptors that induces an IP3 cascade and therefore Ca2+ signalling.

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131
Q

How do gastric acid secretions (from parietal cells, etc.) get into the stomach lumen past the mucus secreted from mucous cells above them in the gastric gland?

A
  • The acid ‘bores’ through the mucus without any lateral spread
  • This stream of H+ is termed a ‘viscous finger’
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132
Q

What things can disturb the mucous barrier in the stomach? What does this result in?

A
  • Aspirin, alcohol and antiinflammatory drugs
  • These can result in gastric ulcers
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133
Q

What are the important electrolytes that are absorbed in the gastrointestinal tract?

A
  • Na+
  • K+
  • Cl-
  • HCO3-
  • Fe2+
  • Ca2+
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134
Q

How much fluid enters the gastrointestinal tract each day? How much of this is excreted?

A
  • 9L (2L ingested and 7L secreted)
  • Only 100ml is excreted in the stool each day
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135
Q

At what points is water absorbed along the gastrointestinal tract?

A

In total, about 8.9L of water are absorbed per day:

  • Small intestine -> About 8.5L of water is reabsorbed here
  • Colon -> About 400ml of water
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136
Q

Does the colon fully utilise its absorptive capacity in reabsorbing water?

A

No, it only reabsorbs about 400ml of fluid per day, which is about 10% of its capacity.

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137
Q

Is the faeces hypertonic or hypotonic?

A

Hypertonic, because water is reabsorbed in the colon, which is a tight epithelium, leaving the faeces hypertonic.

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138
Q

What happens to the water that is absorbed from the gastrointestinal tract?

A
  • Can replace that lost from urination, perspiration and respiration
  • Can be used for subsequent secretions
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139
Q

Draw a diagram to show all of the points that water enters and exits the gastrointestinal tract.

A
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140
Q

Compare the epithelia type, transport type and function of the small intestine and colon/rectum in fluid reabsorption.

A
  • Small intestine
    • Leaky epithelium
    • Lots of paracellular transport
    • Bulk absorptive role -> Absorbs about 8.5L of fluid per day
  • Colon/rectum
    • Tight epithelium
    • Mostly transcellular transport
    • Absorbs about 400ml of fluid per day, which is only 10% of its absorptive capacity
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141
Q

Is the absorption in the small intestine or colon/rectum more susceptible to regulation?

A
  • Colon/rectum
  • Because it is a tight epithelium
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142
Q

Is it just absorptive processes that occur in the intestines?

A

No, there is also:

  • HCO3- secretion in the duodenum
  • NaCl secretion (net) from immature cells at the ends of villi
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143
Q

Describe the mechanism by which water absorption occurs in the small intestine and colon.

A
  • Na+/K+-ATPase on the basolateral membrane creates a hypertonic interstitial fluid
  • Co-transported molecules and ions such as chloride help with this
  • This creates an osmotic gradient for the movement of water from the lumen to the interstitial fluid
  • Water can move via:
    • Transcellular route -> Through aquaporins
    • Paracellular route -> Through tight junctions
  • Water moves from the interstitial fluid to the blood due to Starling forces
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144
Q

Leaky epithelia tend to have a much higher water permeability than tight epithelia. Is this distinction very pronounced betweenthe small intestine (leaky) and colon (tight)?

A

No, the disticntion is not very pronounced.

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145
Q

Describe the principle on which absorption of solutes occurs in the intestines.

A
  • Basolateral Na+/K+-ATPase creates a sodium gradient across the epithelial cells
  • This gradient is utilised by sodium co-transporters and exchangers on the apical membrane that can be used to reabsorb other solutes into the cell
  • These other solutes are then moved acorss the basolateral membrane into the interstitial fluid (and then blood)
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146
Q

What are the different pathways for solute movement across the intestinal epithelium? What proteins are involved?

A
  • Diffusion through channels
    • ENaC (sodium)
    • CFTR (chloride)
  • Na+/H+ exchange
    • NHE (sodium-hydrogen exchanger)
  • Na+-glucose co-transport
    • SGLT (sodium-glucose)
  • Na+-amino acid co-transport
    • System B
  • Na+-chloride co-transport
    • Direct NaCl co-transport (NCC)
    • Indirect co-transport via Cl-/HCO3- (AE, driven by the aforementioned NHE)
147
Q

What is ENaC and what does it do?

A
  • Epithelial sodium channel
  • Allows absorption of sodium into intestinal epithelial cells by diffusion
148
Q

What is CFTR and what does it do?

A
  • Cystic fibrosis transmembrane conductance regulator
  • It is a channels in the apical membrane of intestinal epithelial cells that allows chloride diffusion (out of the cell usually)
149
Q

What is NHE and what does it do?

A
  • Sodium-hydrogen exchanger
  • It is on the apical membrane of epithelial cells in the intestine and moves sodium into the cell while moving hydrogen out of the cell
150
Q

What is SGLT and what does it do?

A
  • Sodium-glucose linked transporter
  • Co-transporter on the apical membrane of epithelial cells that is used to move sodium and glucose into epithelial cells together
151
Q

What is NCC and what does it do?

A
  • Sodium-chloride co-transporter
  • It is on the apical membrane of epithelial cells in the intestine, moving sodium and chloride into the cell
152
Q

What is AE and what does it do?

A
  • Anion exchanger
  • It is usually on the apical membrane of epithelial cells in the intestines and moves chloride into the cell while moving bicarbonate out
153
Q

Are the transport processes the same at all points from the small intestine to the rectum?

A

No, different processes play the dominant role in the duodenum, jejunum, ileum, colon and rectum.

154
Q

What are the different transport processes that play a dominant role at different points along the gastrointestinal tract? [IMPORTANT]

A
  • Duodenum
    • SGLT + AA co-transporters -> Glucose absorption and amino acid absorption
    • NHE
  • Jejunum + Ileum
    • SGLT + AA co-transporters -> Glucose absorption and amino acid absorption
    • NHE with AE -> Chloride absorption
    • NCC -> Chloride absorption
  • Colon
    • NHE with AE -> Chloride absorption
    • Some NCC -> Chloride absorption
  • Rectum
    • ENaC

Note that these divisions are not so clear-cut. It is worth considering the general changes that occur along the GI tract. In the whole small intestine there is amino acid and glucose absorption, with chloride absorbed paracellularly. In the jejunum and ileum, there is also chloride reabsorption through the cell. In the colon, chloride absorption continues, but is is not so much of a sodium-dependent process. Finally, by the rectum there is just sodium reabsorption.

155
Q

After solutes have been absorbed across the apical membrane of intestinal epithelial cells, how do they cross the basolateral membrane?

A
  • Na+/K+ ATPase in transports Na+ into interstitial fluid
  • Other solutes exit the cell through channels and carriers
156
Q

What hormone stimulates sodium reabsorption in the intestines?

A

Aldosterone

157
Q

Draw a summary of all of the transport processes that can occur between the duodenum and rectum.

A
158
Q

What do all the transport processes between the duodenum and rectum rely on?

A

Na+/K+-ATPase and associated K+-channel on the basolateral membrane

159
Q

In Robert Wilkins lectures, what does the slope of arrows on the transport proteins and exchangers indicate?

A

Whether that solute is moving up or down a concentration gradient.

160
Q

Describe the absorptive and secretory processes that occur in the duodenum.

A

All is driven by the basolateral Na+/K+-ATPase on the basolateral membrane.

Absorptive:

  • Amino acids -> Via co-transporter on apical membrane and carrier on basolateral membrane
  • Glucose -> Via SGLT1 on apical membrane and GLUT2 on basolateral membrane
  • Sodium -> Via NHE3 on apical membrane and basolateral Na+/K+-ATPase
  • Chloride -> Via paracellular route due to sodium in the interstitial fluid
  • Potassium -> Via paracellular route

Secretory (in order to neutralise stomach acid):

  • Bicarbonate
    • NHE1 on basolateral membrane moves hydrogen out of the cell
    • This moves the carbonic anhydrase reaction equilibirum to the right, accumulating bicarbonate inside the cell
    • This is added to by the NBC1 (sodium-bicarbonate co-transporter) on the basolateral membrane, which moves more bicarbonate into the cell
    • The bicarbonate moves out of the cell by an AE (bicarbonate-chloride exchanger)
    • The chloride moves back out into the lumen via a CFTR, which allows this secretion to continue
161
Q

Describe the absorptive and secretory processes that occur in the jejunum and ileum.

A

All is driven by the basolateral Na+/K+-ATPase on the basolateral membrane.

Absorptive:

  • Amino acids -> Via co-transporter on apical membrane and carrier on basolateral membrane
  • Glucose -> Via SGLT1 on apical membrane and GLUT2 on basolateral membrane
  • Sodium -> Via NHE3 on apical membrane and basolateral Na+/K+-ATPase
  • Chloride
    • Via paracellular route due to sodium in the interstitial fluid
    • ALSO by AE (Cl-/HCO3- exchanger) and NCC an the apical membrane, then exiting via the KCC1 on the basolateral membrane -> This is the main difference between this and the duodenum
  • Potassium -> Via paracellular route

No secretory function, unlike duodenum.

162
Q

What NHE isoform is on the apical membrane of epithelial cells in the small intestine?

A

NHE3

163
Q

What are the two transport proteins (specifically) involved in the absorption of glucose across epithelial cells in the small intestine?

A
  • SGLT1 on apical membrane
  • GLUT2 on basolateral membrane
164
Q

Aside from AE, what is another exchanger that works in parallel with the NHE of the apical membrance in the jejunum and ileum?

A

DRA

165
Q

Describe the absorptive and secretory processes that occur in the colon and rectum.

A

All is driven by the basolateral Na+/K+-ATPase on the basolateral membrane. Paracellular transport is less important because it is a tight epithelium.

Absorptive:

  • Sodium -> Via ENaC on apical membrane and basolateral Na+/K+-ATPase
  • Chloride
    • Via AE (Cl-/HCO3- exchanger) then exiting via the ClC-2 channel on the basolateral membrane
    • This is driven by removal of H+ by the NHE1 on the basolateral membrane, which shifts the carbonic anhydrase reaction towards producing H+ and HCO3-, which is used by the AE
  • Potassium -> MAY be absorbed via H+/K+ exchanger on the apical membrane, then via the K+/Cl- co-transporter on the basolateral membrane

Secretory:

  • Potassium -> MAY be secreted via potassium channels on the apical membrane, driven by the Na+/K+-ATPase on the basolateral membrane
166
Q

How does the absorption of chloride change from the jejunum and ileum to the colon and rectum?

A
  • It becomes less reliant on the paracellular route and less reliant on sodium in the lumen for co-transport
  • Instead, there is an Na+/H+ exchanger on the basolateral membrane that drives the AE on the basolateral membrane
167
Q

What is the name for the chloride channel on the basolateral membrane of colon and rectum epithelial cells?

A

ClC-2

168
Q

What is the isoform of NHE on the basolateral membrane of colon and rectum epithelial cells?

A

NHE1

169
Q

Is potassium absorbed or secreted in the gastrointestinal tract?

A

It depends on where.

170
Q

Describe how potassium secretion and absorption changes along the length of the gastrointestinal tract.

A
  • Duodenum, jejunumm and ileum
    • Passive reabsorption via the paracellular route
  • Colon and rectum
    • Active absorption by the apical H+/K+ exchanger and basolateral K+/Cl- symporter
    • Active secretion via the basolateral Na+/K+-ATPase and then apical K+ channels in colon
    • Passive secretion via the paracellular route (assuming there is the electrochemical gradient)

The relative importance of these pathways depends on K+ balance and is hormonally controlled.

171
Q

Where in the gastrointestinal tract can potassium be both absorbed and secreted?

A

Colon and rectum

172
Q

How is the balance between potassium absorption and secretion in the colon and rectum controlled?

A
  • Aldosterone stimulates the Na+/K+-ATPase on the basolateral membrane -> Increases potassium secretion
  • Hypokalaemia stimulates absorption
173
Q

Draw a diagram to show how ACTIVE potassium secretion happens in the colon and rectum.

A

NOTE: A small amount of passive secretion can also happen via the paracellular route.

174
Q

Draw a diagram to show how ACTIVE potassium absorption happens in the colon and rectum.

A

NOTE: A small amount of passive absorption can also occur via the paracellular route.

175
Q

Draw a diagram to show bicarbonate secretion in the duodenum.

A
176
Q

Aside from potassium secretion in the large intestine and bicarbonate secretion in the duodenum, what is the other form of secretion you need to know about in the intestines?

A
  • Secretion from cells in crypts of Lieberkuhn
  • These are immature cells found at the base of the villi in the small and large intestines
177
Q

Describe how secretion from cells in the crypts of Lieberkuhn occurs.

A

The mechanism is identical to the mechanism of primary secretion in the acinar cells of the pancreas:

  • Na+/K+-ATPase on the basolateral membrane creates a sodium gradient for the NKCC
  • Basolateral NKCC (Na+-K+-2Cl- co-transporter) accumulates Cl- ions inside the cell
  • Cl- ions diffuse across the apical membrane through channels
  • K+ diffuses out through basolateral channels
  • Na+ ions can also diffuse between cells into the lumen through tight junctions, along the electrical gradient established by Cl- movement
  • H2O follows by osmosis

The net result is essentially the secretion of a dilute saline.

178
Q

Describe how secretion from the crypts of Lieberkuhn cells is clinically relevant. [EXTRA]

A

Secretion can be upregulated by (for example) cholera toxin:

  • Cholera toxin uncouples a G-protein
  • This activates cAMP production
  • cAMP stimulates chloride channels on the apical membrane and potassium channels on the basolateral membrane
  • Excessive secretion ensues
  • This leads to diarrhoea

Toxins that increase intracellular calcium have the same effect.

179
Q

Describe the daily intake of calcium, the amount secreted in the GI tract, the amount absorbed in the GI tract and the amount excreted in the kidneys.

A
  • Dietary intake = 1g/day
  • Intestinal secretions = 0.15g/day
  • Intestinal absorption = 0.35g/day
  • Renal excretion = 0.2g/day
180
Q

Where in the GI tract does calcium absorption occur and is it up or down a concentration gradient?

A
  • Upper duodenum
  • Against a concentration gradient
181
Q

Describe the mechanism for calcium absorption in the duodenum. [IMPORTANT]

A
  • Ca2+ crosses apical membrane via ECaC (epithelial calcium channels)
  • Ca2+ binds in the cytosol to calbindin, which transports it across the cytosol to the basolateral membrane
  • Ca2+ exits into the interstitial fluid via a Ca2+-ATPase and NCE (sodium-calcium exchanger)
  • Ca2+ can also be internalised in vesicles, which travel across the cytosol and fuse with the basolateral membrane
182
Q

Through what channels is calcium absorbed from the GI tract at the duodenum?

A

ECaC (Epithelial calcium channels)

183
Q

After calcium is absorbed from the GI tract across the apical membrane of duodenum cells, what does it bind to in the cytosol?

A

Calbindin

184
Q

What transporter is used to move calcium out from duodenum cells (after absorption from the GI tract) into the interstitial fluid?

A
  • Ca2+-ATPase
  • NCE (Sodium-calcium exchanger)
185
Q

How is calcium absorption from the GI tract at the duodenum regulated?

A

The vitamin D-derived protein calcitriol stimulates ECaC (epithelial calcium channel) and calbindin (chaperone protein across the cytosol) synthesis.

186
Q

What is the importance of iron in the human body?

A

Involved in:

  • O2 transport
  • DNA synthesis
  • Electron transport
  • Binding to proteins in order to prevent damage from free radicals
187
Q

Where in the GI tract does iron absorption happen?

A

Duodenum

188
Q

Describe the mechanism for iron absorption in the duodenum.

A
  • Fe2+ crosses the apical membrane by the bivalent cation transporter DCT1, which is dependent on the H+ gradient generated by the acidity of the duodenum lumen
  • Any Fe3+ in the lumen is reduced to Fe2+ by iron reductase on the apical membrane, so it can be taken up by DCT1
  • Heme can also be taken up by a haem transporter on the apical membrane, after which it is converted to Fe2+ by haem oxidase
  • The Fe2+ in the cell is converted to Fe3+ by ferroxidase
  • Fe3+ can now enter one of two pathways:
    • Absorptive pathway
      • Fe3+ binds to iron-binding proteins, which take it to the basolateral membrane
      • A complex of two proteins (hephaestin and IREG1) transports the Fe3+ into the blood
      • In the blood, the Fe3+ is bound to transferrin for transport
    • Storage pathway
      • Fe3+ binds to ferritin in the cytoplasm, where it is stored
      • When needed, the Fe3+ can be mobilised and taken to the hephasetin/IREG1 complex for transport into the blood
189
Q

In which form can iron in the GI tract be absorbed into the epithelial cells?

A
  • Fe2+
  • Haem
190
Q

How is Fe3+ in the GI lumen converted to Fe2+ for absorption into the duodenum epithelial cells?

A

Iron reductase

191
Q

What transporter is used to absorb Fe2+ into epithelial cells in the duodenum?

A

Divalent cation transporter DCT1 -> This is a co-transporter that requires a H+ gradient generated by the acidity of the duodenum lumen

192
Q

What other ions (except for iron) can divalent cation transporter be used to absorb?

A

Cu2+ and Zn2+

193
Q

What transporter is used to absorb haem into epithelial cells in the duodenum?

A

Haem transporter

194
Q

How is haem converted to Fe2+ in the epithelial cells of the duodenum after absorption?

A

Haem oxidase

195
Q

What enzyme converts Fe2+ into Fe3+ in the cytoplasm of the epithelial cells of the duodenum?

A

Ferroxidase

196
Q

What protein is used to transport Fe3+ across the cytoplasm of epithelial cells of the duodenum (in the absorptive pathway)?

A

Iron-binding protein

197
Q

What protein is used to store Fe3+ in the cytoplasm of epithelial cells of the duodenum (in the storage pathway)?

A

Ferritin

198
Q

What protein is used to transport Fe3+ across the basolateral membrane of epithelial cells of the duodenum?

A

Hephaestin/IREG1 complex

199
Q

What is iron bound to in the blood for transport?

A

Transferrin

200
Q

What is the only site of iron regulation in the body?

A

Epithelial cells of the duodenum

201
Q

Describe how the epithelial cells of the duodenum are involved in iron regulation.

A
  • Iron can be stored in the “storage pathway” in these cells, bound to ferritin protein
  • If iron in the body drops, it can be transported into the blood via the hephaestin/IREG1 complex
  • If iron in the body rises, then it remains stored in the storage pathway until the epithelial cells are shed every 5 days
202
Q

Where in the GI tract are carbohydrates, proteins, fats, minerals and vitamins absorbed?

A

Small intestine

203
Q

What brush border enzymes in the small intestine are involved in the digestion of lactose?

A
  • Lactase
204
Q

Describe how the small intestine has an increased surface area for nutrient absorption.

A
  • Have folds of mucosa
  • On these folds, there are villi
  • On the villi, the epithelial cells have a ruffled apical (‘brush border’) membranes
205
Q

What is the name for intestinal absorptive cells?

A

Enterocytes

206
Q

How often are enterocytes turned over?

A

Every 3-7 days

207
Q

What are the different ways of digesting and absorbing different nutrients from the GI tract? Give an example of a nutrient processed in each way.

A
  • None
    • Glucose
  • Digestion in the lumen, then absorption across the cell
    • Proteins to amino acids
  • Digestion on the apical membrane, then absorption across the cell
    • Disaccharides, such as sucrose
  • Absorption into the cell, then hydrolysis intracellularly
    • Di- and tripeptides
  • Digestion in the lumen, then resynthesis intracellularly after absorption
    • Triglycerides
208
Q

What are the different carbohydrate components that the body needs to be able to digest and absorb?

A
  • Starch
  • Sugars -> e.g. lactose
209
Q

What are the bonds in starch?

A

α-1,4 and α-1,6 glycosidic bonds

210
Q

Describe the digestion of starch.

A
  • Salivary amylase initiates starch digestion, which is completed by pancreatic amylase
  • This yields maltose, maltotriose and α-limit dextrins
  • Brush border enzymes on the epithelial cells hydrolyse these products and sucrose and lactose
  • This releases glucose, fructose and galactose, which can be absorbed
211
Q

Why can’t amylase digest starch completely?

A

Because it can only hydrolyse α-1,4 internal bonds, not the α-1,6 bonds.

212
Q

What are the 3 products of starch digestion?

A
  • α-dextrins
  • Maltotriose
  • Maltose
213
Q

What are some of the epithelial brush border enzymes for the digestion of carbohydrates in the small intestine?

A
  • Glucoamylase
  • Sucrase
  • Isomaltase
  • Trehalase
  • Lactase
214
Q

What brush border enzymes in the small intestine are involved in the digestion of α-dextrins?

A
  • Glucoamylase
  • Sucrase (Only α-1,4 dextrins)
  • Isomaltase
215
Q

What brush border enzymes in the small intestine are involved in the digestion of maltotriose?

A
  • Glucoamylase
  • Sucrase
  • Isomaltase
216
Q

What brush border enzymes in the small intestine are involved in the digestion of maltose?

A
  • Glucoamylase
  • Sucrase
  • Isomaltase
217
Q

What brush border enzymes in the small intestine are involved in the digestion of sucrose?

A
  • Sucrase
218
Q

What brush border enzymes in the small intestine are involved in the digestion of trehalose?

A
  • Trehalase
219
Q

Summarise all of the brush-border enzymes involved in the digestion of carbohydrates.

A
  • Glucoamylase, sucrase and isomaltase are all involved in the digestion of α-dextrins, maltotriose and maltose
  • Lactose is digested by lactase
  • Sucrose is digested by sucrase
  • Trehalose is digested by trehalase
220
Q

What is another name for glucoamylase?

A

Maltase

221
Q

What reaction does lactase catalyse?

A

The hydrolysis of lactose to glucose and galactose.

222
Q

What reaction does glucoamylase (maltase) catalyse?

A
  • The hydrolysis of maltose to 2 glucose monomers
  • The hydrolysis of maltotriose to 3 glucose monomers
223
Q

What reaction does sucrase-isomaltase catalyse?

A

It is a two enzyme complex.

Sucrase:

  • Hydrolysis of sucrose to glucose and fructose
  • Hydrolysis of maltose to glucose monomers
  • Hydrolysis of maltotriose to glucose monomers

Isomaltase:

  • Hydrolysis of α-limit dextrins, maltose and maltotriose to glucose monomers
224
Q

How are glucose, galactose and fructose absorbed across the epithelial cells in the small intestine?

A

Glucose and galactose:

  • Absorbed through SGLT1 (a sodium-dependent carrier)
  • If the glucose concentration in the lumen increases, GLUT2 can also be inserted into the apical membrane

Fructose:

  • Absorbed through GLUT5 facilitated diffusion proteins
225
Q

How are glucose, galactose and fructose transported across the basolateral membrane of epithelial cells of the small intestine?

A

Through GLUT2 transporters.

226
Q

When in the GI tract is carbohydrate absorption usually complete by?

A

Mid-jejunum

227
Q

How does lactose intolerance arise?

A

A deficiency in the lactase enzyme.

228
Q

Draw a diagram to summarise the absorption of glucose, galactose and fructose across epithelial cells in the small intestine.

A
229
Q

What is the clinical relevance of an SGLT1 mutation and why?

A

It results in glucose and galactose malabsorption.

230
Q

What are the two types of SGLT in the body and where is each found?

A
  • SGLT1 -> In the small intestine, proximal tubule (S3 segment), RBC, heart
  • SGLT2 -> In the proximal tubule (S1 segment), liver and brain
231
Q

In SGLT1 mutations, is glucose overspill witnessed?

A

No, because there are also SGLT2 transporters in the proximal tubule.

232
Q

How are fructose and glucose uptake in the small intestine related?

A
  • Fructose usually moves across the apical membrane down its concentration gradient via GLUT5 proteins
  • When this needs to happen against a concentration gradient, the GLUT5 can act as an exchanger by using the glucose that has accumulated inside the cell (by the SGLT1 protein) to energise the uptake of fructose
233
Q

When are GLUT2 proteins inserted into the apical membrane of enterocytes and how?

A
  • When luminal glucose concentration is high, glucose can move down its concentration gradient across the apical membrane
  • This requires GLUT2 proteins (as oppose to the SGLT1 co-transporter), meaning that they must be inserted into the apical membrane
  • This is a calcium-dependent process
234
Q

Describe the digestion of proteins.

A
  • Pepsin in the stomach breaks down proteins into smaller polypeptides
  • These are further broken down by pancreatic endopeptidases (e.g. trypsin) and exopeptidases (e.g. carboxypeptidases) -> This produces oligopeptides (2-6 amino acids) and amino acids
  • The oligopeptides can be further broken down by brush border enzymes on the enterocytes of the small intestine to yield dipeptides and tripeptides
  • The amino acids, dipeptides and tripeptides can now be absorbed into the enterocytes
235
Q

What is the main gastric enzyme involved in protein digestion? What does it do?

A

Pepsin -> It is involved in the breakdown of proteins to polypeptides.

236
Q

What are the two classes of protein-digesting enzymes produced by the pancreas?

A
  • Endopeptidases
  • Exopeptidases
237
Q

What are the main pancreatic endopeptidases?

A
  • Trypsin
  • Chymotrypsin
  • Elastase
238
Q

What is the main pancreatic exopeptidases?

A

Carboxypeptidases

239
Q

Describe how amino acids are absorbed across enterocytes.

A
  • Cross apical membrane via sodium-dependent co-transporters or sodium-independent facilitated diffusion proteins
    • There are carriers for the different classes of amino acids (neutral, cationic, basic)
  • Cross basolateral membrane through passive facilitated diffusion proteins
240
Q

Describe the absorption of dipeptides and tripeptides across enterocytes.

A
  • Cross the apical membrane via PepT-1 (a hydrogen-dependent co-transporter)
  • Cytosolic peptidases convert the peptides to amino acids
  • Now these can cross the basolateral membrane through passive facilitated diffusion proteins
241
Q

What is the name for the hydrogen-dependent di/tripeptide co-transporters on the apical membrane of enterocytes? What drives them?

A
  • PepT-1
  • They are driven by the acidity of the lumen of the GI tract
242
Q

By what point in the GI tract is the absorption of the products of digestion complete?

A

By the end of the jejunum

243
Q

Is co-transport with sodium the only way for amino acids to be absorbed from the small intestine lumen into enterocytes?

A
  • No, they can also be absorbed using facilitated diffusion proteins
    • These are sodium independent
  • They can function using exchange mechanisms too
    • The accumulation of one amino acid in the enterocyte can be used to energise the uptake of a different amino acid by exchange via the facilitated diffusion protein
244
Q

What are the different types of apical membrane proteins for the absorption of amino acids into enterocytes?

A

Sodium-dependent co-transporters:

  • B -> Neutral amino acids
  • B0+ -> Neutral and cationic amino acids
  • XAG- -> Anionic amino acids

Sodium-independent facilitated diffusion proteins:

  • b0+ -> Neutral and cationic amino acids
  • y+ -> Cationic

NOTE: The sodium-independent facilitated diffusion proteins can be driven by the exchange of amino acid (that has been accumulated inside the enterocyte) back into the intestinal lumen.

245
Q

What are the different types of basolateral membrane proteins for the absorption of amino acids across enterocytes?

A

Sodium-indepedent facilitated diffusion proteins:

  • asc = Neutral amino acids
  • L = Neutral amino acids
  • y+ = Cationic amino acids
246
Q

What is Hartnup disease? What are the symptoms?

A
  • Mutation in system B (sodium-dependent co-transporter for the absorption of neutral amino acids into enterocytes)
  • This means that L-phenylalanine and other neutral amino acids cannot be reabsorbed from the renal tubule, so they are excreted in the urine
  • In the GI tract, this is not a problem because PepT-1 is functioning in parallel, allowing uptake of these amino acids as dipeptides and tripeptides
247
Q

What is cystinuria? What are the symptoms?

A
  • Mutation in system B0+ and system b0+ (sodium-dependent co-transporter or sodium-independent facilitated diffusion protein for the absorption of neutral and cationic amino acids into enterocytes)
  • This means that L-arginine and other neutral/cationic amino acids cannot be reabsorbed from the renal tubule, so they are excreted in the urine
  • In the GI tract, this is not a problem because PepT-1 is functioning in parallel, allowing uptake of these amino acids as dipeptides and tripeptides
248
Q

What is the importance of intracellular peptidases in the GI tract?

A

They hydrolyse the dipeptides and tripeptides that are taken up into enterocytes, so that amino acids are produced that can cross the basolateral membrane and enter the blood.

249
Q

Is the rate of amino acid absorption from the GI tract greater when they are presented as amino acids or when they are presented as dipeptides?

A

Dipeptides, because of the PepT-1 carrier that increases the rate of absorption.

250
Q

What is the effect of amino acid absorption into enterocytes in the form of dipeptides and tripeptides? Why?

A
  • They depolarise the membrane and acidify the cell
  • This is because the PepT-1 protein is a co-transporter with H+, so intracellular H+ is increased
251
Q

Describe the process of lipid digestion.

A
  • Muscular movements of stomach emulsify TAGs (transformation into emulsion of oil droplets in water), which is aided by lingual lipases
  • In the small intestine, bile salts break down large lipid droplets into smaller lipid droplets, increasing the surface area for lipase activity
  • Pancreatic lipase digests triglycerides to monoglycerides and free fatty acids
  • Colipase (from the pancreas) coordinates binding of lipase to emulsion
  • The products form mixed micelles
  • Micelles diffuse to an unstirred acidic layer near the apical membrane and dissociate at the cell surface
252
Q

What are the lipases involved in the digestion of lipids?

A
  • Lingual lipases
  • Pancreatic lipases
253
Q

What is colipase?

A
  • A protein co-enzyme required for optimal enzyme activity of pancreatic lipase
  • It is secreted from the pancreas
254
Q

What is the role of bile salts in lipid digestion?

A
  • Bile salts are detergents that decrease surface tension to make smaller oil droplets
  • i.e. They break large lipid droplets into smaller ones
255
Q

What causes micelles to dissociate at the apical membrane?

A

There is an unstirred layer of acid at the apical membrane of enterocytes. This causes the micelles to dissociate.

256
Q

What products of lipid digestion are not incorporated into micelles? What happens to them?

A
  • Glycerol and short-chain fatty acids
  • They can move to the apical membrane and diffuse through it, then do the same at the basolateral membrane
257
Q

What are the components of a micelle, aside from bile salts?

A
  • Cholesterol
  • Lysophospholipids
  • Long-chain fatty acids
  • Monoglycerides
258
Q

Describe what happens to the components of micelles after they are absorbed into enterocytes.

A
  • The triglycerides are reassembled in the SER
  • Apoproteins are produced in the RER
  • The triglycerides and apoproteins combine to form chylomicrons

Note: The components that are not included in micelles (short-chain fatty acids and glycerol) pass straight across the cell and diffuse across the basolateral membrane into the blood.

259
Q

Describe the path of chylomicrons after they are synthesised in enterocytes.

A
  • They are exported by the Golgi apparatus, pass into lymphatic capillaries
  • The lymph drains back into left subclavian vein via thoracic duct
260
Q

Where in enterocytes are triglycerides resynthesised?

A

SER

261
Q

Where in enterocytes are apoproteins synthesised?

A

RER

262
Q

How are chylomicrons exported from enterocytes?

A

Via the Golgi apparatus.

263
Q

Instead of chylomicron secretion, what happens in enterocytes during fasting?

A

Smaller, very low density lipoproteins (VLDLs) are secreted into the lymphatic system instead.

264
Q

What are some examples of water-soluble vitamins?

A
  • Thiamine B1
  • Riboflavin B2
  • B12
  • Vitamin C
  • Folic acid
265
Q

What are some examples of lipid-soluble vitamins?

A

Vitamins A, D, E, K

266
Q

How can water-soluble vitamins be absorbed from the GI tract?

A
  • Passive diffusion via the paracellular route
  • Transcellularly, via specific Na+-coupled co-transporter proteins
  • Binding to specific apical receptors (B12)
267
Q

What is another name for vitamin B12?

A

Cobalamin

268
Q

Describe how vitamin B12 (water-soluble) is absorbed from the GI tract across enterocytes.

A

Another name for vitamin B12 is cobalamin:

  • Cobalamin is bound to proteins in food
  • Gastric secretions include IF (intrinsic factor)
  • A cobalamin-IF complex forms
  • The complex can then interact with a receptor on the apical membrane of enterocytes
  • The receptor and the bound complex can then be endocytosed into the cell
  • These can then be processed by a lysosome to degrade the receptor and IF
  • The cobalamin is then packaged with transcobalamin II (a chaperone protein) for exocytosis into the blood
269
Q

How can fat-soluble vitamins be absorbed from the GI tract?

A
  • They are presented for absorption dissolved in bile micelles
  • They diffuse across the apical membrane
  • In most cases, they are incorporated back into chylomicrons for export out of the cell
270
Q

What mechanical events must occur for continence of the gut tube and bladder to happen?

A
  • Compartments under low pressure to allow storage of waste
  • Sphincters closed to prevent outflow
271
Q

What mechanical events must happen in order for voidance of the gut tube and bladder to occur?

A
  • Increase in pressure of storage compartment so as to drive outflow
  • Sphincters open to allow outflow
272
Q

What are some important features that are required for correct continence and voidance of the gut and bladder?

A
  • Sensory systems to inform about filling
  • Reflex pathways to generate voiding
  • Higher control centres to enable voluntary voiding
  • Appropriate muscles
273
Q

What prompt the urge for defecation?

A

Movement of faeces into the rectum .

274
Q

What is the rectum?

A

Expandable organ for the temporary storage of faeces.

275
Q

What are the two sphincters in the rectum and what is the innervation of each?

A
  • Internal anal sphincter
    • Smooth muscle
    • Controlled by ANS
  • External anal sphincter
    • Striated muscle
    • Under voluntary control
276
Q

How does the anal canal relate to the rectum?

A

The anal canal is the final part of the rectum.

277
Q

What morphological structures does the anal canal contain?

A
  • Longitudinal folds called anal (or rectal) columns
  • These are joined at their distal ends by transverse folds
278
Q

At the distal ends of the anal columns in the anal canal, there are transverse folds. What do these mark out?

A

They mark the point of transition between columnar epithelial epithelium (inside) and the stratified squamous epithelium (outside).

279
Q

How can haemorrhoids occur in the rectum?

A

The anal canal features a network of veins. During defecation, strain can increase the pressure, causing distension of the veins and increasing the likelihood of haemorrhoids.

280
Q

What are the two main plexuses of the enteric nervous system?

A
  • Meissner’s plexus -> Submucosal
  • Auerbach’s plexus -> Myenteric
281
Q

What is a plexus (in the context of the enteric nervous system)?

A

A system of afferent sensory neurons, interneurons and motor neurons.

282
Q

Does the enteric nervous system function on its own?

A
  • It can, but it can also be stimulated by sympathetic and parasympathetic fibres.
  • There are also afferent fibres that feed back information to control centres in the brain.
283
Q

Draw the structure of the enteric nervous system.

A
284
Q

Where do the symapthetic and parasympathetic neurons supplying the GI tract have their ganglia?

A
  • Parasympathetic -> Near the organ
  • Symapthetic -> Proximal ganglia near the spinal cord
285
Q

What is the effect of parasympathetic and sympathetic stimulation of the GI tract?

A
  • Parasympathetic nervous system stimulates smooth muscle
  • Sympathetic nervous system inhibits smooth muscle

Except for the sphincter of the anorectum!

286
Q

Describe the parasympathetic, sympathetic and somatic nerves that innervate the distal gut. What does each do?

A
  • Parasympathetic
    • Pelvic splanchnic nerves (S1-S4)
    • Promotes defecation: stimulation of rectal motility and relaxation of internal sphincter.
  • Sympathetic
    • Nerve roots L1-L3, passing through the mesenteric and pelvic plexuses
    • Promotes continence: inhibition of rectal smooth muscle and contraction of internal sphincter.
  • Somatic
    • Pudendal nerve (S2-S4)
    • Controls the external anal sphincter
287
Q

What parasympathetic nerve (including nerve roots) supplies the distal gut (i.e. anorectal canal)?

A
  • Pelvic splanchnic nerves
  • S1-S4
288
Q

What sympathetic nerve roots supply the distal gut (i.e. anorectal canal)?

A

L1-L3

289
Q

What somatic nerve (including nerve roots) supplies the external anal sphincter?

A
  • Pudendal nerve
  • S2-S4
290
Q

Is the rectum full most of the time? What triggers the defecation reflex?

A
  • No, the rectum is empty most of the time but faeces are moved into the rectum from the sigmoid colon by peristaltic contractions.
  • Distension of the rectal walls triggers the defecation reflex.
291
Q

Describe the defecation reflex.

A

Distension of the rectum by faeces triggers two reflex loops:

  • Short reflex loop:
    • Activation of the myenteric plexus of the enteric nervous system of the sigmoid colon and rectum
    • This increases local peristalsis
    • As a result, more faeces is moved into the rectum, ready for defecation
  • Long reflex loop:
    • Stimulation of parasympathetic motor nerves in sacral region, including the pelvic splanchnic nerves -> This leads to increased peristalsis of the large intestine so there is more faecal material pushed into the rectum and also causes relaxation of the internal anal sphincter
    • Stimulation of somatic motor neurons, including the pudendal nerve -> This leads to contraction of the external anal sphincter
292
Q

What other bodily actions does the defecation reflex also stimulate?

A
  • Taking a deep breath
  • Closure of the glottis
  • Contraction of abdominal wall muscles to push faecal content of the colon downwards
293
Q

What is a major function of the sensory innervation of the anorectal canal?

A

Anorectal sampling of the contents.

294
Q

What is the purpose of anorectal sampling?

A

Enables discrimination between gas, liquid and solid -> This allows fine-tuning of the defecation reflex accordingly.

295
Q

What things can happen if the external anal sphincter remains constricted for a prolonged period of time?

A
  • Peristaltic contraction diminishes until additional expansion of the rectum restimulates the defecation reflex.
  • Rectal content may return back to the colon.
296
Q

What pressure is required to trigger the defecation reflex?

A

Around 15mmHg.

297
Q

At what rectal pressure does defecation become forced? Why is this important?

A
  • Above around 55 mmHg, the external anal sphincter is forced to relax
  • Occurs in infants and in adults with severe spinal cord injury
298
Q

What are some features that affect faecal continence?

A
  • Consistency of stool
  • Delivery of colonic content to the rectum
  • Rectal capacity and compliance
  • Anorectal sensation
  • Function of the anal sphincter mechanism
  • Muscles and nerves of the pelvic floor
299
Q

What are 3 examples of clinical conditions relevant to faecal continence?

A
  • Diarrhoea
  • Spinal cord pathologies
  • Hirschprung’s syndrome
300
Q

What is diarrhoea and what causes it?

A
  • An increase in stool liquidity and weight (200 g/day)
  • Caused by:
    • Increased fluid secretion by the small or large intestine
    • Decreased water reabsorption by intestines
    • These can be due to bacterial or viral infection of the colon or small intestine
  • Liquids are more difficult to contain and the chemical stimulus to defecate is high
301
Q

Name two spinal cord pathologies that may affect faecal continence.

A
  • Spinal cord injury
  • Multiple sclerosis
302
Q

What is Hirschprung’s disease and what causes it?

A
  • Congenital polygenic disorder
  • Caused by arrest of the caudal migration of the neural cell crest (precursors of ganglion cells)
  • Characterised by congenital agenesis of the Auerbach’s plexus in the rectum and upwards -> Results in an “aganglionic” rectum that fails to relax in response to faeces
  • Main problem is constipation
303
Q

What is the effect of noradrenaline and acetylcholine on the smooth muscle of the rectum? What is the experimental evidence for this?

A
  • Noradrenaline causes relaxation of the smooth muscle -> Administering NA to a sample of rectum muscle caused contraction to stop
  • Acetylcholine stimulates contraction of the smooth muscle -> Administering carbachol (a cholinomimetic drug) to a sample of rectal muscle caused contraction to happen
304
Q

What adrenoceptors are found on rectal smooth muscle?

A

β2

305
Q

What is the effect of noradrenaline and acetylcholine on the smooth muscle of the internal anal sphincter? What is the experimental evidence for this?

A
  • There is a sample of smooth muscle that has a baseline amount of contraction
  • Noradrenaline causes contraction of the smooth muscle -> Administering NA to a sample of rectum muscle caused contraction to increase
  • Acetylcholine stimulates relaxation of the smooth muscle -> Administering carbachol (a cholinomimetic drug) to a sample of rectal muscle caused decreased contraction
306
Q

What adrenoceptors are found on internal anal sphincter smooth muscle?

A

α1

307
Q

Describe an experiment that involved electrical stimulation of the internal anal sphincter and what this showed.

A
  • A sample of the IAS showed a baseline amount of contraction
  • When electrically stimulated, the muscle relaxed
  • In the presence of atropine or guanethidine, this relaxation still happened -> Therefore the relaxation is not mediated by ACh or NA
  • In the presence of TTX, this relaxation did not happen -> Therefore the relaxation is mediated by nerves (but not resulting in ACh or NA)
  • Thus, another mediator must be present:
  • When L-NOARG (an inhibitor of nitric oxide synthase) is present, relaxation does not occur -> Therefore NO is involved in the relaxation
308
Q

What does this experiment show?

A
  • The dots show points where electrical stimulation of the internal anal sphincter occurs, causing relaxation of the sphincter
  • L-NOARG is an inhibitor of nitric oxide synthase -> When added, it causes the inhibition of the relaxation
  • L-arginine inhibits the effects of L-NOARG since it is a substrate for the NOS pathway -> When added, it causes relaxation to resume
  • Thus, we can see that NO is important in internal anal sphincter relaxation
309
Q

Describe the synthesis of NO and its action.

A
310
Q

How does acetylcholine cause relaxation of the internal anal sphincter?

A

It causes release of NO from a nitrergic nerve terminal, which then acts to relax the smooth muscle.

311
Q

Draw a summary of the control of the internal anal sphincter.

A
312
Q

What are some drugs that can be used to relax the internal anal sphincter?

A
  • Topical NO donors
  • Topical sildenafil (phosphodiesterase 5 inhibitor) -> PDE is involved in degradation of cGMP (involved in NO synthesis)
  • Ca2+ channels blockers -> Calcium is involved in smooth muscle contraction
  • Topical bethanechol (muscarinic receptors agonist)
  • Adrenoreceptor modulators (e.g. indoramin, α1-adrenoreceptor blocker)
313
Q

What are some drugs that can be used to contract the internal anal sphincter?

A
  • α1-adrenoreceptor agonist (e.g. phenylephrine)
314
Q

Why might you use drugs to increase or decrease internal anal sphincter contraction?

A
  • Decrease contraction -> To treat anal fissures
  • Increase contraction -> To treat incontinence
315
Q

What adrenoreceptor modulator can be used to increase anal sphincter contraction?

A

Phenylephrine (α1 agonist)

316
Q

What adrenoreceptor modulator can be used to decrease anal sphincter contraction?

A

Indoramin (α1 blocker)

317
Q

Drugs that affect GI motility and secretions tend to act on what two main points?

A
  • Local enteric plexus
  • A control centre in the central nervous system that communicates with the plexus
318
Q

What is oesophageal reflux and why does it occur? [EXTRA]

A
  • The reflux of gastric contents, especially acid, into the oesophagus.
  • It often produces a characteristic burning sensation in the midline of the chest, known to older generations as “heartburn”.
  • It seems to happen because the cardiac “sphincter” of the stomach is relatively easily overcome by high pressure in the stomach.
  • So, reflux is common after large fatty meals, common in obese people.
319
Q

What are peptic ulcers?

A

An area of necrosed lining of the stomach, proximal duodenum or oesophagus caused by gastric secretions (especially the acid component).

320
Q

Describe the symptoms of peptic ulcers. [EXTRA]

A
  • Can be asymptomatic
  • Range of pain from vague discomfort to significant pain.
  • They can also bleed if the acid erodes beyond the epithelium into the underlying tissues -> Symptoms relate to the bleeding rather than to the ulcer itself:
    • Iron-deficiency anaemia
    • Melaena -> Black stool, stained by digested haemoglobin (more serious anaemia)
    • Occasionally an ulcer may present as an acute GI bleed, if an artery or arteriole in the base of the ulcer crater has been eroded by the acid
  • Less commonly, perforation can occur where the whole thickness of the intestinal wall is eroded, leading to inflammation of the peritoneum (called peritonitis) that lines the peritoneal cavity
321
Q

What are the main ways of treating peptic ulcers?

A

You reduce the effects of the stomach acid by:

  • Direct antacids
  • Histamine antagonists
  • Blockers of H+-K+ ATPase
322
Q

Give some examples of antacids that can be used to treat peptic ulcers.

A
  • Aluminium hydroxide [IMPORTANT]
  • Magnesium hydroxide (‘Milk of magnesium’)
  • Magnesium trisilicate
323
Q

What are some of the advantages and disadvantages of use of antacids to treat peptic ulcers?

A

Advantages:

  • Rapid relief of symptoms

Disadvantages:

  • Relief is short-term and mild
  • Does not address the underlying problem
  • Associated with side effects
324
Q

What are some mucosal protector drugs and what are their advantages and disadvantages in treating peptic ulcers? [EXTRA?]

A
  • Examples: Sucralfate (physical barrier), misoprostol (prostaglandin PG-E1 analogue)

Advantages:

  • Rapid relief of symptoms without antacid side-effects.
  • Slightly longer duration of relief than antacids.

Disadvantages:

  • Weak protective effect
  • Relief still short-lived
325
Q

Why is suppresion of acid secretion from the stomach justified in treating peptic ulcers?

A

Antacids do not provide relief for a long enough period for the ulcers to heal -> Long-term suppression of acid secretion allows time for this to happen.

326
Q

What are the main types of drugs used to treat peptic ulcers by inhibition of acid secretion? [IMPORTANT]

A
  • Histamine antagonists (e.g. ranitidine)
  • Inhibitors of H+/K+-ATPase (e.g. omeprazole)
  • Muscarinic antagonists (e.g. pirenzepine) [EXTRA]
327
Q

Give an example of H+/K+-ATPase inhibitors and how they work.

A
  • Omeprazole
  • They inhibit the H+/K+-ATPase, which is the primary source of acid secretion in the stomach
  • Therefore, they are the most potent suppressors of acid secretion, and the most commonly used in the UK to treat peptic ulcers
328
Q

Give an example of histamine (H2 receptor) antagonists and how they work.

A
  • Ranitidine
  • Block the amplifying effect of the mast (ECL) cells on parietal cell stimulation, and so substantially reduce acid secretion without completely blocking it
  • They are used to treat peptic ulcers
329
Q

Give an example of anti-muscarinic agents used to treat peptic ulcers and explain why they are now so rarely used.

A
  • Pirenzepine
  • Act on both the mast (ECL) cell and the parietal cell to inhibit acid secretion
  • Have widespread systemic parasympathetic side-effects, and so are relatively little used now
330
Q

Is there evidence for the idea that H. pylori bacteria cause peptic ulcers?

A
  • Yes, and several hypotheses have been put forward to explain the link between H. pylori and ulcers: at present there is no agreement on the mechanism.
  • A paradox is that H. pylori is present in stomach and intestine of many people who do not develop ulcers, but eradication of the bacterium from a patient with established ulcers substantially lowers the risk of recurrence (from 35% to 2% in 12 months).
331
Q

Describe the chemotherapy used to treat H. pylori that have lead to peptic ulcers.

A

Antibiotics are combined with drugs to suppress the symptoms of the ulcer:

  • Amoxicillin/clarithromycin and metronidazole -> Antibiotics
  • Omeprazole -> H+/K+-ATPase inhibitor
332
Q

What are some ulcerogenic drugs (drugs that can lead to peptic ulcers as a side-effect)? How do these work?

A
  • Steroids and NSAIDs (non-steroidal anti-inflammatory drugs)

These cause peptic ulcers because:

  • Secretion of gastric mucus (that usually has a protective role for the stomach) is stimulated by local prostaglandins
  • Steroids and NSAIDs reduce prostaglandin formation and therefore increase the risk of peptic ulcer formation.
333
Q

What are some particular NSAIDs and steroidal drugs that can increase the risk of peptic ulcers?

A
  • Aspirin [IMPORTANT]
  • Ibuprofen and naproxen
  • Glucocorticoids (corticosteroids)
334
Q

NSAIDs can increase the risk of peptic ulcers. How can the risk of this be reduced? [EXTRA?]

A
  • “Enteric coated” aspirin -> Aspirin coated with a substance that does not dissolve in the stomach but does dissolve in the duodenum. So, although the aspirin will still reduce the formation of gastric prostagladins, it will not have the direct damaging effect on the gastric mucosa.
  • Misoprostol -> Synthetic prostaglandin
335
Q

What are the 4 main types of gastrointestinal motility?

A
  • Myogenic regulation
  • Regional regulation by the enteric nervous system and GI hormones
  • Migrating motility complex (MMC) [EXTRA]
  • Intestinal reflexes
336
Q

What is myogenic regulation of gastrointestinal motility and how does it work?

A
  • The smooth muscle of the GI tract responding to stretch, such as occurs when a bolus of food passes
  • Neurally controlled (by the enteric plexus) over very short distances
  • Dilation in front of bolus, constriction behind
337
Q

How does regional regulation of gastrointestinal motility (non-reflex) work?

A
  • The enteric plexus receives input from sensors within the intestinal wall and can also control motility over short distances, long segments, or the whole length of the intestine.
  • This control can be in response to:
    • The chemical constituency of the food
    • The physical consistency of the food (e.g. how digested)
    • The presence of toxins or substrates that trigger activity of the enteric immune system
  • All of these plexus-regulated motility patterns are subject to modulation by local gastrointestinal hormones.
338
Q

What is the migrating motor complex (MMC)? [EXTRA]

A

A wave of activation spreading caudally from the stomach, regulated by a gastric pacemaker. It is not typically part of the motility pattern seen during digestion of a meal, but occurs:

  • during long gaps between meals
  • in anticipation of a meal
  • frequently during a period of fasting or hunger

This motility pattern appears to have a kind of “housekeeping” function, preventing stagnation of intestinal contents and therefore helping to maintain a healthy gut flora.

339
Q

What are intestinal reflexes and how do they work?

A
  • Regional and local reflexes exist within the intestine to control movement of food and the emptying of the gut.
  • For example, the rate of gastric emptying may be influenced not only by the contents of the stomach but also by the contents of the duodenum – for example, whether the duodenum still contains food from the previous wave of gastric emptying, and whether the luminal pH has returned to alkaline levels.
  • Again, some of these “reflexes” are actually mediated by local hormones, but many are functions of the enteric plexus.
340
Q

What are some examples of patterns of gut movement triggered by the enteric nervous system and GI hormones?

A
  • Regional segmentation
  • Localized + Longer peristalsis
  • Localized reverse peristalsis (even in normal digestion)
  • Reverse peristalsis, especially in the proximal small intestine, as part of the vomiting reflex.
341
Q

Describe how gastric motility and emptying is controlled. [IMPORTANT]

A

It largely undergoes regulation by the enteric plexus and GI hormones that influence the plexus:

  • Different rates of emptying according to the contents of the meal (fatty meals stay in the stomach for much longer than mainly-protein meals)
  • Co-ordination of gastric motility with the opening of the pyloric sphincter (fatty meals produce long periods of churning against a closed sphincter)
  • Pyloric sphincter is opened in the vomiting reflex when there is reverse peristalsis in the small intestine

Local and regional reflexes (also mediated by the enteric plexus) play a role:

  • Emptying can be influenced by the contents of the duodenum (e.g. whether the duodenum still contains food from the previous wave of gastric emptying and whether the luminal pH has returned to alkaline levels)
342
Q

What are two important forms of motility in the small intestine? [IMPORTANT]

A
  • Segmentation
  • Pendular activity
343
Q

What is chyme?

A

The partially-digested food mass in the stomach.

344
Q

What is segmentation of small intestinal motility? [IMPORTANT]

A
  • To ensure that the body receives enough nutrients from its food, the small intestine mixes the chyme using smooth muscle contractions called segmentations.
  • Segmentation involves the mixing of chyme about 7 to 12 times per minute within a short segment of the small intestine so that chyme in the middle of the intestine is moved outward to the intestinal wall and contacts the mucosa.
  • In the duodenum, segmentations help to mix chyme with bile and pancreatic juice to complete the chemical digestion of the chyme into its component nutrients.
345
Q

What is the pendular activity of the small intestine? [IMPORTANT]

A

The way in which waves of constriction sweep up and down the small intestine, like a pendulum.

346
Q

What is the most important form of motility in the large intestine? How is this triggered? [IMPORTANT]

A
  • Peristalsis
  • It is triggered by distension and mediated by the enteric nervous system
347
Q

What are some types of drug that can have an effect on GI motility? [IMPORTANT]

A
  • Anti-emetics
  • Laxatives
  • Anti-diarrhoeal drugs
  • Parasympathomimetics
  • Opiates
348
Q

What is the effect of anticholinergic drugs on GI motility?

A

They inhibit motility, leading to constipation.

349
Q

What is the effect of opiates on GI motility?

A
  • They inhibit motility, leading to constipation.
  • This is because they reduce neural activity.
350
Q

What are some of the most common causes of constipation?

A
  • Diet low in fibre
  • Dehydration
  • Lack of exercise -> Connection between poor abdominal muscle tone and prolonged intestinal transit time
  • Anticholinergic drugs
  • Opiates
351
Q

What are some of the complications of constipation? [EXTRA]

A
  • Haemorrhoids (“piles”)
  • Diverticular disease (small herniations in the wall of the colon, apparently caused by high pressures in a constipated gut)
  • May be associated with colon cancer
352
Q

What are some possible non-drug treatments for constipation? [EXTRA]

A
  • Improving diet:
    • Increasing fibre content
    • Increasing fluid intake
  • More exercise
353
Q

What are some types of laxative? How do they work? [IMPORTANT]

A
  • Lubricants (e.g. paraffin)
    • Ease the passage of the faeces
  • Bulk formers (e.g. sterculia (Normacol))
    • Increase the fibre content of the faeces and also help to retain water, so softening the stool
  • Osmotic laxatives (e.g. magnesium salts)
    • Retain water in the colon and so soften the stool
  • Motility stimulants (e.g. bisacodyl)
    • Usually cholinergic agonists, often with some direct effect on smooth muscle.
354
Q

When should anti-diarhhoael drugs not be used?

A
  • It’s not appropriate to use anti-diarrhoeal drugs if there is an infection in the gut -> The diarrhoea is part of the normal physiological mechanism for expelling the infection.
  • Most commonly used as part of the treatment of non-infectious inflammatory processes in the gut, such as inflammatory bowel disease (Crohn’s disease and ulcerative colitis).
355
Q

What are the different types of anti-diarrhoael drugs? How do they work? [IMPORTANT]

A
  • Adsorbent agents
    • Absorb water and ions and result in a more solid stool, which is less irritating to the gut wall
    • e.g. Kaolin
  • Anti-cholinergic agents
    • Inhibit gut motility and secretion and can act as antispasmodics in irritable bowel disease and inflammatory bowel disease
    • e.g. Hyoscyamine
  • Opiates
    • Strongly inhibit gut motility
    • e.g. Loperamide
356
Q

What is an anti-emetic drug?

A

One that is useful against vomiting and nausea.

357
Q

What are some cases of vomiting and nausea that might or might not require treatment using anti-emetics?

A
  • Toxins or infections in the gut or in the blood
    • Anti-emetic drugs not useful
  • Drugs that induce nausea and/or vomiting as a side-effect of their action (e.g. opiates and cytotoxic drugs used in treatment of cancer)
    • Anti-emetics useful
  • Disturbances of balance (e.g. travel sickness and infections of the labyrinth and vestibule of the inner ear)
    • Anti-emetics useful
358
Q

Why are anti-emetics not usually used to treat vomiting due to infections of the GI tract?

A

Because vomiting is often a helpful way to remove the infection from the gut.

359
Q

What are the main categories of anti-emetic action?

A
  • Cholinergic muscarinic antagonists (in general, less potent than the next two)
  • Dopamine (mainly D2) antagonists
  • Serotonin 5HT-3 antagonists

And the fourth category is mainly restricted to use in disturbances of the inner ear (including travel sickness):

  • Histamine H1 antagonists

In other words, most anti-emetic drugs work on the CNS and gut motility also.

360
Q

What stimulates gall bladder motility?

A

CCK

361
Q

What activates intestinal peptidases?

A

Enterokinase

362
Q

What is typically used as an oral rehydration solution?

A

Isosmotic salt/glucose solution

363
Q

What are some defensive mechanisms in the alimentary tract?

A
  • Taste
  • Gastric acid
  • Mucus
  • Mucosal immune system

YEAR 1 - Physiology and Pharmacology (Anton) (13 decks)

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