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PHARM 213 Gastrointestinal > 2. Structure & Function of the GIT > Flashcards

2. Structure & Function of the GIT Flashcards

1
Q

GIT responsible for

A
  • Absorption of nutrients & water into the body

- Elimination of body waste

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2
Q

Digestive system GIT: 2 sections

A

Upper GI:

  • Oesophagus
  • Stomach – secretes protein digesting enzymes called proteases & strong acids to aid in food digestion
  • Duodenum – part of small intestine

Lower GI:

  • Jejunum & ileum – part of the small intestine
  • Large intestine, include cecum, colon & rectum – absorption & storage
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3
Q

Regulation & functions of the GIT

A
  • Extrinsic & intrinsic autonomic efferent innervation of wall of intestine
  • Enteric nervous system of GI tract innervates smooth muscle & mucosa
  • Efferent & afferent neurons are organised in intramural plexuses

Vagal preganglonic fibers: Increase GI transit, motility & secretion
Sympathetic postganglionic fibres: Slow/inhibit GI transit, motility & secretion

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4
Q

Transport across GI epithelia

A
  • Stomach – epithelia lining in the stomach, secrete HCl into the stomach lumen, which after a meal becomes pH 1
  • Small intestine – those lining the small intestine transport products of digestion (e.g. glucose & amino acids) into the blood
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5
Q

Proper function of GIT requires:

A
  • Normal secretions of HCl & digestive chemicals by gastric glands within stomach
  • Adequate protection of the stomach & intestinal lining from caustic digestive enzymes & strong acidic environment
  • Normal movement of substances (via muscle contractions) through the GI tract
  • Normal passage of nutrients & water through the GI walls into the body
  • Interference with these functions can result in GI disorders such as nausea, indigestion, ulcers, diarrhoea, constipation & malnutrition
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6
Q

Stomach - 4 regions

A

4 regions:

  • Cardia – superior, medical portion
  • Fundus – portion superior to stomach-oesophageal junction
  • Body – area between the fundus & the curve of the J
  • Pylorus – antrum & pyloric canal adjacent to the duodenum
  • Pyloric sphincter – guards exit from stomach
  • Rugae – ridges & folds in relaxed stomach
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7
Q

Stomach: Submucosa & Serosa

A 
Submucosa:
- Denser connective cells
- Contain fat cells & mast cells, 
lymphoid cells & eosinophilic 
leukocytes
- Rich in blood & lymph vessels
Serosa:
- Covers outer part of stomach
- Consists of mesothelium & thin 
propria of loose connective 
tissue
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8
Q

Stomach: Mucosa

A

Within mucosa:

  • Gastric pits
  • Gastric glands - within fungus & body of stomach
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9
Q

Composition of gastric glands (4):

A
  1. Neck mucous cells:
    - Secrete mucus
    - Prevents stomach digesting itself
  2. Chief cells (or Zymogenic):
    - Synthesise & secrete hydrolytic enzymes which are activated at acid pH
    - Enzymes include gastric lipase, rennin & pepsin, which is secreted as pepsinogen and activated in the lumen
  3. Parietal cells (or oxyntic cells):
    - Secrete HCl
  4. Enteroendocrine cells:

Entochromaffin-like (ECL) cells:
- Respond to gastrin released by G-cells (Gastrin cells in gastric gland) & release histamine, stimulates parietal cells to produce gastric acid

Entochromaffin cells:

  • Found throughout GI tract
  • Act as sensory transducers – activate mucosal processes of both intrinsic & extrinsic primary afferent neurons through release of 5-hydroxytryptamine (5-HT) -> gastrointestinal mucosal motility
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10
Q

Enteroendocrine cells (mucosal epithelium of stomach/duodenum)

A

Secretes peptide hormones controlling several functions of the GI system:

Cholecystokinin:

  1. It slows down emptying of the stomach by acting on the pyloric sphincter
  2. It stimulates bile release from the gallbladder & the secretion of pancreatic enzymes

Gastrin:

  1. It stimulates the secretion of HCl by parietal cells
  2. It stimulates insulin secretion by B cells of the islets of Langerhans
  3. Gastrin also stimulates gastric motility & growth of the mucosal cells

Secretin:

  1. It stimulates pancreatic bicarbonate secretion
  2. It enhances insulin secretion by B cells of the islets of Langerhans
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11
Q

Acidification of the stomach lumen by parietal cells in the gastric lining

A
  • Apical membrane of parietal cells contains a H+/K+ ATPase (P-class pump) as well as Cl- & K+ channel proteins
  • Note the cyclic K+ transport across the apical membrane – K+ ions are pumped inward by the H+/K+ ATPase & exit via a K+ channel
  • Basolateral membrane contains an anion antiporter that exchanges HCO3- & Cl- ions
  • Together these different transport proteins acidifies the stomach lumen while maintaining the neutral pH & electroneutrality of the cytosol
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12
Q

Mechanism regulating secretion of HCl by gastric parietal cells

A

Receptors for acetylcholine (M3), histamine (H2), & gastrin (G) interact when activated by agonists to increase availability of Ca2+ & stimulate the H+, K+-ATPase of the luminal membrane

Acid secretion can be decreased by blockade of:

  • M3 receptors (anticholinergics – e.g. Propantheline – used with other medications to treat
  • H2 receptors (e.g. Ranitidine i.e. Zantac, a H2 blocker for GERD
  • cAMP

H+, K+-ATPase (e.g. most commonly prescribed proton pump inhibitors are omeprazole (Prilosec) & esomeprazole (Nexium)

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13
Q

Small intestine (3 subdivisions)

A
  • Longest portion of the alimentary canal (~5m)
  • Site of most enzymatic digestion & absorption

3 subdivisions:

  1. Duodenum – 1st 25 cm after pyloric sphincter
  2. Jejunum – next 2/5 of length
  3. Ileum – last 3/5 of length & empties into large intestine
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14
Q

Small intestine: Increasing surface area (3)

A
  1. Large folds are pilcae circulares
  2. Microscopic finger-like projections are villi
    - Each villus is covered with columnar epithelial cells interspersed with goblet cells
    - Epithelial cells at tips of villi are exfoliated & replaced by mitosis in crypts of Lieberkühn
    - Inside each villus are lymphocytes, capillaries & central lacteal
  3. Apical hair-like projections are microvilli
    - Project from apical surface of each epithelial cell creating a brush border
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15
Q

Small intestine: Cell types (4)

A
  1. Intestinal absorptive cells
  2. Goblet cells:
    - Secretes mucus to neutralise stomach acid
  3. Paneth cells:
    - Key effectors of innate mucosal defence
    - Occur in small groups in depths of crypts
    - Cytoplasm is basophilic with large acidophilic granules (contain lysozyme)
  4. Basal granular cells (Argenaffin or Entochromaffin, enteroendocrine cells)
    - Site of serotonin synthesis, storage, & release
    - Secretes cholecystokinin (stimulates Gall bladder to release bile, also pancreas)
    - Secretin (stimulates pancreatic ducts to release acid neutraliser)
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16
Q

Small intestine: Mechanical Digestion (2)

A
  1. Peristalsis:
    - Weak & slow
    - Occurs mostly because pressure at pyloric end is greater than at distal end
  2. Segmentation:
    - Major contractile activity of SI
    - Contraction of circular smooth muscle to mix chyme

NB: Chyme is semifluid mass of partly digested food matter that is expelled by the stomach, through the pyloric valve, into the duodenum

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17
Q

Large intestine

A
  • Extends from ileocecal valve at end of small intestine to anus
  • No digestive function
  • Absorbs H2O, electrolytes, vitamins B & K, & folic acid
  • Internal surfaces has no villi beyond the ileocecal valve & does not have folds, except in the rectum
  • Has large proportion of microflora (~1014 commensal bacteria of 400 species)
    + These produce folic acid & vitamin K
    + Ferment indigestible food to produce fatty acids
    + Reduce ability of pathogenic bacteria to infect large intestine
    + Antibiotic therapy can affect not only intended target position, but also commensal bacteria – extent of impact on non-target microbial populations, depends on type of antibiotic used
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18
Q

Duodenum

A
  • Main part of secretion & absorption takes place in small intestine, where intestinal enzymes together with pancreatic & bile secretions break down proteins & bile & emulsify fats into micelles

Duodenum has:
- Brunner’s glands (duodenal glands) – produce bicarbonate
- Pancreatic juices – contains bicarbonate
+ Function is to neutralise HCl of the stomach

Neural control – both pancreas & gallbladder stimulated by vagus (e.g. acetylcholine) -> contents secreted into duodenum

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19
Q

Pancreas (dual organ) - Exocrine

A

Exocrine – acinar cells form the exocrine pancreas & make up the bulk of the organ (98%)

Produces pancreatic fluid:

  • Watery alkaline solution
  • pH 8
  • Neutralises chyme
  • Important in digestion

Electrolytes:

  • Primarily HCO3-
  • Enzymes – trypsin, chymotrypsin, amylase, lipases, nucleases

Ionic composition of pancreatic fluid is rate dependent:

  • Higher flow – more HCO3-
  • Lower flow – more Cl-

Pathophysiology of cystic fibrosis:

  • Abnormalities in Cl- channels (CFTR) in pancreatic ductural cells-channel fail to open
  • No passage of HCO3- & water flux
  • Failure of fluid & electrolyte secretion

Note: Secretin from intestine released into bloodstream stimulates pancreas to secrete HCO3

20
Q

Pancreas (dual organ) - Endocrine

A

Endocrine – made up of the collections of cells in the islets of Langerhans

4 main cell types:

  • Beta-cells – secrete insulin (make up 60-75% of islet cells)
  • Alpha cells – secrete glucagon
  • Delta cells – secrete somatostatin which acts on parietal cells to decrease acid secretion
  • PP cells – secrete pancreatic polypeptide which inhibits gallbladder contraction & pancreatic exocrine secretion

NB: Glucagon counterbalances actions of insulin

  • ~4-6 hours after eating, glucose levels in the blood decrease, triggering the pancreas to produce glucagon
  • Glucagon signals the liver & muscle cells to stored glycogen back into glucose
21
Q

Activation of Pancreatic Juice Enzymes

A

Complete digestion of food requires action of both pancreatic & brush border enzymes

Pancreas produces 2 major proteases – trypsin & chymotrypsin

  • These are synthesised & packaged into secretory vesicles as inactive forms (i.e. zymogens – trypsinogen & chymotrypsinogen)
  • Trypsinogen is activated by brush border enzyme, enterokinase (EN)
  • Trypsin in turn activates other pancreatic zymogens
22
Q

Liver

A

Largest internal organ

Hepatocytes form hepatic plates that are 1 – 2 cells thick
- Plates are separated by sinusoids which are fenestrated & permeable to proteins - Contain phagocytic Kpuffer cells

Damaged liver can regenerate itself from mitosis of surviving hepatocytes, but sometimes can’t regenerate

  • E.g. Severe alcohol abuse or viral hepatitis
  • Often leads to liver fibrosis, which can progress to cirrhosis

Pharmacy applications for alcoholics:

  • Disulfiram (Antabuse), which makes you sick when you drink & increases heart rate, flushing (warmth & redness)
  • Naltrexone (ReVia, Vivitrol), interferes with the pleasure you get from drinking - Also used to combat craving for opiate drugs
23
Q

Hepatic portal system

A

Capillaries in digestive tract drain into the hepatic portal vein which carries blood to liver

Food absorbed in small intestine is delivered first to liver via hepatic portal vein

24
Q

Enterohepatic circulation

A
  • Recirculation of compounds between liver & intestine
  • Many compounds are released in bile, then reabsorbed in small intestine & returned to liver to be recycled
  • Liver excretes drug metabolites into bile to pass out in faeces
25
Q

Enterohepatic Bile Circulation

A

Bile juice – secretion & stimulation

  • Important in digestion & absorption of lipids
  • Contains bile salts, bile acids, mucus bilirubin from broken down RBC, phospholipids

Bile salts:

  • Synthesised in liver from cholesterol, then stored in gallbladder before they enter duodenum
  • Bile salts return to liver vial portal vein to be actively taken up & secreted again

Under hormonal control:

  • Food is released by stomach into duodenum (chyme), duodenum releases cholecystokinin (main stimulant for gallbladder to release bile)
  • Gastrin & secretin also stimulate bile secretion
26
Q

Differences between small & large intestine Refer to word doc

A
  • Absorption of non-electrolyte nutrients occurs mainly in small intestine
  • Whereas both the small & large intestine absorbs water & electrolytes (Na+, Cl- etc)
  • Small intestine – absorbs net amounts of water, Na+, Cl- & K+ & secretes HCO3-
  • Large intestine – absorbs net amounts of water, Na+, Cl-, & secretes both K+ & HCO3-
27
Q

Fluid balance in the GIT

A
  • Inflow - ~8.5 L/day presented to small intestine
  • Outflow – reabsorbed by small intestine (jejunum) ~6.5 L/day
  • ~2 L/day is reabsorbed in the colon
  • Thus leaving ~0.1 L/day in faeces
  • By the time the contents enters the large intestine ~80% of this fluid has been absorbed
28
Q

Major sites of absorption

A

Water:

  • Duodenum – very little net absorption of water occurs here
  • Jejunum – is more active than ileum in water absorption
  • Colon – water absorption

Na+:

  • Can be absorbed along the entire length of the intestine
  • Jejunum – the net rate of absorption of Na+ is the highest
  • Ileum – less absorption

HCO3-:

  • Proximal duodenum – secreted
  • Jejunum - absorbed
  • Ileum – secreted
  • Colon – secreted

CI-:

  • Jejunum – absorbed
  • Ileum – absorbed
  • Colon – absorbed

K+:

  • Jejunum – absorbed
  • Ileum – absorbed
  • Colon – secreted when in lumen < 25 mg or absorbed

Ca2+:
- Is absorbed by all segments of the intestine especially in the duodenum & jejunum

Iron:
- Non-heme iron is particularly absorbed in the duodenum

Mg2+:

  • Can be absorbed along the entire length of the intestine
  • Ileum – largest absorption
  • Duodenum – smaller absorption
  • Colon – even smaller absorption

Phosphate:

  • Can be absorbed along the entire length of the intestine
  • Duodenum > Jejunum > Ileum
  • Jejunum – largest absorption as it is long

Copper:
- Jejunum – largest absorption

Net absorption occurs in mature epithelial cells near the tip of the villi

Net secretion of electrolytes & water occurs in the Lieberkühn crypts

29
Q

Absorption & secretion of electrolytes & fluid by intestine

A

Intestine – 1o organ of H2O & nutrient absorption

  • Important role in fluid & electrolyte balance
  • Na2+ absorption major driving force for absorption of fluid/H2O
  • Na2+ enters intestinal cells by diffusion & active transport
30
Q

Transepithelial movement of water & solutes – active & passive mechanisms (2)

A

Either absorptive or secretory

  1. Transcellular:
    - Must move across 2 membranes in series
    - Solutes, across at least one membrane is active
  2. Paracellular:
    - Movement passive via tight junctions
31
Q

Absorption of water

A

Primarily in the jejunum

  • Entirely by osmosis
  • Coupled to solute movement
  • Occurs via transcellular or paracellular routes
  • Paracellular predominate mode of absorption
32
Q

Transport of Na+ into enterocytes (intestinal absorptive cells) (4)

A
  1. Na+ dependent co-transport with glucose, galactose, amino acids, or volatile fatty acids
    NB: Transport with glucose is basis for oral rehydration therapy for diarrhoea
  2. Na+/H+ exchange (HCO3- stimulated Na+ absorption)
  3. Coupled Na+Cl- absorption
  4. Na+ channel, which transports Na+ against an electrochemical gradient
33
Q

Electrogenic nutrient coupled Na+ absorption

A
  • Transport of glucose: lumen -> blood
  • Glucose imported against its concentration gradient from intestinal lumen to apical surface by a 2-Na+/one-glucose symporter located in the microvillar membranes
    + As Na comes in glucose & H2O are dragged in (transcellular)
  • Glucose, movement is mediated by by GLUT2, glucose transporter
  • SGLT1 = Sodium-glucose transporter

Note: E.coli does not affect glucose-stimulated Na+ absorption

34
Q

Parallel Na-H & Cl – HCO3 (ileum & proximal colon)

A

Cl- exchanger – downregulated in adenomas (DRAs or also called SLC26A3)

Primary method of Na absorption between meals:
- Does not contribute to postprandial (after meal) Na absorption, which is mediated primarily by nutrient-coupled transporters

Electroneutral absorption of Na:
- Not inhibited by luminal glucose or HCO3-

Electroneutral absorption of Na regulated by:

  • cAMP & CGMP & Ca2+ - increases in each decrease NaCl absorption
  • Increase in Aldosterone (mineralocorticoid produced from adrenal cortex) and decrease [Ca2+] increases absorption of Na

Note: Decrease in NaCl absorption important in diarrheal disorders:
- E.g. Heat-labile enterotoxin produced by E.coli Toxin activates adenyl cyclase & increases cAMP -> decrease/inhibition NaCl absorption

35
Q

Passive/electroneutral Cl- absorption

A
  • Closely linked to Na+ absorption
  • Paracellular or transcellular
  • Passive or active
  • Active generally involves Cl-HCO3-
36
Q

Modes of Cl- absorption by the intestine (4):

A
  1. In voltage-dependent Cl- absorption, Cl- may passively diffuse from lumen to blood across the tight junctions, driven by the lumen-negative transepithelial voltage (paracellular route). H2O follow via paracellular route
    Alternatively, Cl- may diffuse through apical & basolateral Cl- channels
  2. In the absence of a parallel Na-H exchanger, electroneutral Cl-HCO3 exchange at the apical membrane results in Cl- absorption & secretion
  3. Electroneutral NaCl absorption can mediate Cl- absorption in the interdigestive periods. Intracellular pH (pHi) couples the 2 exchangers
37
Q

Dysfunction of fluid absorption in the GI tract – diarrhoea (3)

A

From Greek work diarrhoea meaning “a flowing through”

Many definitions:

  1. > 200 g/day faeces
  2. 0.2 L/day faecal water
  3. 3 or more liquid bowel movements per day (WHO)
38
Q

Causes & origins of diarrhoea

A

Primary insult: Defects in absorption, secretion or motility; loss of fluid results in loss of Na+, K+, HCO3-

Small intestine origin – voluminous:
- Since intestinal contents are relatively high in K+, profound diarrhoea is associated with both hypokalaemia, as well as systemic dehydration

Large intestinal origin – small volume diarrhoea

Osmotic diarrhoea:

  • Results from disturbances of absorption
  • Occurs when non-absorbable, osmotically active substance is ingested

Secretory diarrhoea:

  • Results from disturbances in secretion
  • Increase in active secretion or there is an inhibition of absorption
39
Q

Oral Rehydration Therapy (ORT)

A

Based on principle that intestinal absorption of sodium (& thus of other electrolytes & water) is enhanced by active absorption of certain food molecules such as:

  • Glucose or
  • I-amino acids (derived from breakdown of proteins/peptides)

This process continues to function during secretory diarrhoea
- So patients with secretory diarrhoea who drink isotonic salt solution that contain no source of glucose or amino acids, sodium is NOT absorbed and the fluid remains in the gut

Isotonic solution of Glucose + Salt -> glucose-linked sodium absorption occurs -> absorption of water & other electrolytes

40
Q

Principle of ORT for diarrhoea #1 (4)

A

Sodium (Na+) & glucose are both required for efficient uptake

  1. Glucose is required here for Na+ ions to be efficiently taken-up by the intestinal epithelium 2 Na+/one-glucose symporter (SGLT1) located in the microvillar membranes
  2. Within intestinal epithelial cell Na+ is pumped by active transport by the Na+/K+ ATPase pump
    Na+/K+ ATPase pump moves 3 Na+ in exchange for 2 K+
  3. This then causes a “downhill” Na+ gradient within the cell
  4. SGLT1 uses energy produced by the Na+ gradient to transport glucose into the cell against the glucose gradient
41
Q

Principle of ORT for diarrhoea #2 (3)

A

Sodium (Na+) & glucose are both required for efficient uptake

  1. GLUT uniporter then transports glucose across epithelial cell membrane
  2. SGLT1 requires 2 Na+ to co-transport one molecule of glucose (or can be galactose)
  3. If no Na+ then glucose NOT absorbed
42
Q

Summary: Principle behind oral rehydration solution

A
  • Glucose increases intestinal salt & H2O transport via Na+/glucose cotransporter
  • Without glucose, intestinal sodium is not absorbed

UNICEF/WHO Oral rehydration salts (ORS):

  • Sodium chloride 3.5 g
  • Sodium bicarbonate 2.5 g
  • Potassium chloride 1.5 g
  • Glucose 20 g
43
Q

Summary: Intestinal fluid & electrolyte movement

A
  • Small intestine – a net absorber of water, Na+, Cl- & K+ but it is a net secretor of bicarbonates
    + Reabsorbs 6.5 L fluid/day
  • Human colon – carries out net absorption of water, Na+ & Cl- with few exceptions, but it carries out net secretion of K+ & bicarbonate
    + Reabsorbs 1.9L (~2L) fluid/day
  • Fluid movement – always coupled to active solute movement
  • Solute movement – may be coupled to fluid movement by solvent drag, a phenomenon in which the dissolved solute is swept along by bulk movement of the solvent (i.e. water)
44
Q

Summary of Anatomy & Cell types of Small Intestine vs Large Intestine

A

Surface area of small intestine at 3 levels:

  1. Folds of Kerckring
  2. Villi & crypts of Lieberkühn
  3. Microvilli

Surface area of large intestine (colon) at 3 levels:

  1. Semilunar folds
  2. Crypts (but not villi)
  3. Microvilli
45
Q

Summary: Glucose is absorbed in small intestine by absorptive cells: Intestinal Epithelial cells (enterocytes)

A

Glucose is absorbed by sodium glucose co-transport mechanism

  • Na/K pump generates low Na inside cell
  • This causes then Na to being transported into cell with glucose by transporter
  • The Na+/K+ pump removes Na+ from cell by active transport -> [Na+] kept low
  • ATP provides energy to move Na+ against its concentration gradient, from low to high concentration
    + 3x Na+ are moved outwards & 2x K+ are moved inwards for each ATP hydrolysed to ADP + Pi
  • Example of a P-class pump
46
Q

Summary: Coupled transport of sodium & glucose in intestinal epithelial cells

A
  • Although nutrient-independent sodium absorption across the brush border membrane of intestinal epithelial cells is impaired in patients with diarrhoea, coupled transport of sodium & glucose is preserved, allowing absorption of salt & water provided by oral rehydration solutions (ORSs)
  • Sodium-glucose transporter type I (SGLT1) mediates the transport of glucose against its concentration gradient by coupling it to sodium transport
  • Sodium that enters the cell is pumped into the blood via Na+/K+ ATPase (adenosine triphosphatase) pump in the basolateral membrane, maintaining the sodium electrochemical gradient that drives the sodium-glucose cotransport mechanism
  • Transport of glucose into the blood is facilitated by glucose transporter type II (GLUT2)

PHARM 213 Gastrointestinal (9 decks)

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