GI intro

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GI intro
2011-02-26 00:31:40

GI physiology
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  1. How many liters of fluid go into the GI tract/day? Where do they come from?
    • 8L/day, 99% absorbed (82% sm. intestine, 17% lrg intestine)
    • 1200 ml from drinking water
    • 1500 ml from saliva
    • 2000 ml from gastric secretion
    • 500 ml from bile
    • 1500 ml from intestinal secretions
  2. 2 basic types of GI regulation?
    • -- Neural regulation
    • a. extrinsic nervous system: autonomic nerves.
    • b. The intrinsic/enteric nervous system: local neural network - neurotransmitters and neuromodulators
    • -- Hormones and Paracrine Factors
  3. Cephalic Phase
    • Anticipation!
    • parasympathetic efferent pathway activates enteric nerves -> parietal cells secrete HCl and stimulate the G cells to secrete the hormone gastrin => increased motility
  4. Gastric Phase
    • Food enters stomach
    • Amino acids and peptides -> G cells secrete gastrin -> parietal cells secrete HCl, activate stomach motility.
    • Distention -> vagus nerve -> enteric nervous system -> parietal cell secretion of HCl and G cell secretion of gastrin
    • Mechanoreceptors -> enteric nerves -> G cells and parietal cells.
    • Caffeine -> parietal cells -> HCl.
  5. Intestinal Phase
    • Distention
    • acidity
    • hyperosmolarity
    • fat/amino acids
    • -> neural reflexes and hormone secretion
  6. Secretion of salivary
    • No hormonal reg
    • Parasympathetic - facial and glossopharyngeal nerves release ACh, bind to muscarinic receptors
    • Sympathetic - thoracic spinal nerves T1-3, B adrenegeric receptors
  7. Swallowing
    Secondary peristalsis
    • Pressure -> afferent to brainstem -> efferent to pharynx
    • Stuck food, contractions w/o swallowing
  8. Anatomical and physiological divisions of stomach
    • Fundic/cardiac, Body, Antrum
    • Orad - top half, relaxes w/LES, expands
    • Caudad - perstaltic contractions
  9. BER/slow waves
    • Parasympathetic activation, and secretion of gastrin and motilin depolarize Vm
    • Sympathetic activation hyperpolarizes Vm
  10. HCl secretion in stomach
    • parietal cell - H+/K+ ATPase, Cl- channel on luminal, HCO3-/Cl exhanger on serosal
    • ACh, gastrin, histamine - # H+/K+ ATPases
    • pepsinogen -> pepsin by HCl
  11. vitamin absorption
    • B12: water-soluble, must form complex w/IF to be absorbed - other H2O-soluble vits are taken up by Na+ exchangers
    • Fat-soluble - chylomicrons ->lymph -> systemic circulation
  12. Vomiting (3 steps)
    • Autonomic - increased salivation, sweating, increased heart rate, skin pallor, and nausea
    • Retching: Deep breath, close glottis, and elevation of soft palate. Abs contract. Relaxation of LES, body of stomach -- stomach contents into esophagus
    • Vomiting: large pressure increase, UES opens, reverse peristalsis
  13. Pyloric sphincter reg
    • acidity: enteric neural reflex, contraction
    • fat content: CCK, contraction
    • hyperosmotic chyme: contraction
  14. Motility of small intestine
    • Chyme after a meal - higher frequency contractions at proximal end than distal (9-12/min)
    • MMC - during fasting, 1/90min, sweep undigested contents
  15. hormonal and paracine reg of sm intestine motility
    • a. Fasting -> secretion of motilin -> MMC
    • b. Eating -> CCK, gastrin, insulin – segmentation and peristaltic contractions.
    • c. Eating -> serotonin secretion from enterochromaffin cells of the GI and enteric NS -> stimulate motility.
    • d. Stress -> adrenal medulla -> Epi -> inhibits motility
  16. Exocrine pancreas: HCO3-
    • Na+/H+ ATP-dependent transport basolateral, HCO3-/Cl- luminal, Cl- channel luminal
    • Acid in sm. intestine -> Secretin increases HCO3- secretion and insertion of Cl- channels
  17. Exocrine pancreas
    • zymogens secreted from acinar cells
    • trypsinogen activated by membrane-bound enterokinase
    • Trypsin then converts other zymogens to amylase, lipase, cholesterol ester hydrolase, phospholipase A2,(fats) chymotrypsin, elastase, carboxypeptidase(proteins), ribonucletidases
    • FA,AA -> CCK -> inc. zymogens
  18. Bile
    • released in duodenum
    • bile salts, phospholipids, cholesterol, bile pigments, and inorganic ions (e.g., Na+, K+, Ca2+, Cl- and HCO-3)
    • 95% reabsorbed in ileum to liver via enterohepatic circulation
    • CCK causes contraction of gallbladder + relaxation of sphincter of Oddi
  19. large intestine contractions
    • before meal, illeocecal sphincter is closed, reflex relaxation, then distention causes contraction
    • Segmentation - 1/30min, slow
    • Mass movement - gastrin, CCK after meal
    • Defecation - mechanoreceptor reflex
  20. Saccharide absorption
    • a. GLUT-5: facilitated diffusion of fructose across luminal membrane
    • b. SGLT-1: secondary active transport of glucose and galactose across luminal membrane
    • c. GLUT-2: facilitated diffusion of monosaccharides across basolateral membrane
    • d. Role of Na-K-ATPase on basolateral membrane in setting up diffusion gradient for SGLT-1 function
  21. visceral v. parietal peritoneum
    • visceral peritoneum: same blood & lymphatic vasculature and visceral nerve supply as the organ it is attached to, autonomic, insensitive to pain
    • parietal: same as abdominal wall, somatic
  22. peritoneal cavity
    peritoneal ligament
    • potential space between layers of peritoneum. Thin layer of fluid lubricates, allows organs to move
    • Connects organ to peritoneum or organs to each other
  23. Intraperitoneal organs
    Retroperitoneal organs
    • almost completely covered with visceral peritoneum
    • outside the peritoneal cavity (external or posterior to the parietal peritoneum) and are only partially covered by peritoneum.
  24. Celiac trunk branches
    • splenic -> left gastroepiploic
    • common hepatic
    • -> gastroduodenal -> posterior superior pancreaticoduodenal, anterior superior pancreaticoduodenal, R gastroepipoic
    • -> hepatic proper -> right gastric, R and L hepatic (R hepatic gives off cystic)
    • L gastric
  25. Superior mesenteric artery branches
    • -> ileal and jejunal branches (15-18)
    • -> ileocolic, right colic, middle colic, common inferior pancreaticoduodenal ileocolic - ileal, colic, anterior cecal, posterior cecal and appendicular
  26. Inferior mesenteric artery branches
    superior rectal, sigmoids and left colic. marginal artery forms an anastomosis w/ superior mesenteric artery
  27. Portal vein
    • Formed at L2 by superior mesenteric + splenic veins (+ inf mesenteric)
    • -> liver -> hepatic vein -> IVC
  28. anastomosis occurs in 4 areas
    • (1) between L gastric (portal) and esophageal (caval) veins
    • (2) between paraumbilical (portal) and epigastric (caval) veins
    • (3) between colic (portal) and retroperitoneal (systematic) veins
    • (4) between the superior rectal (portal) and middle & inferior rectal (caval) veins.
  29. Busiprone
    • 5HT1A partial agonist
    • treatment for dyspepsia/anxiolytic
  30. Aortic (pre-aortic) plexus ganglia
    • Only sympathetics synapse here, parasymps (vagal and pelvic splanchnics) run thru to synapse @ organ
    • celiac, aorticorenal, sup mesenteric, inf mesenteric
  31. Enteric Nervous System
    • Ganglion cells communicate thru interneurons
    • Submucosal (Meissner’s) plexus and the myenteric (Auerbach’s) plexus
    • Symps modulate (not part of ENS) - sphincter tone (smooth muscle) and vascular tone
  32. Path of bile
    hepatocytes, bile canaliculi, (interlobular) bile ductules, left and right hepatic ducts, common hepatic duct, common bile duct, hepatopancreatic ampulla/sphincter, major duodenal papilla and finally into the duodenum.
  33. Foregut
    • distal esophagus, stomach, 1st & 2nd parts of the duodenum, liver, gallbladder and pancreas
    • NOT spleen
    • greater splanchnics (T5-9), anterior vagal trunk
  34. Midgut
    • from 3rd part of duodenum to prox 2/3 of transverse colon
    • lesser and least splanchnics (T10-12), posterior vagal trunk
  35. 5 differences between ileum and jejunum
    • Vasa recta are long in the jejunum and short in the ileum.
    • Arterial arcade loops are large & few in the jejunum and short & many in the ileum.
    • Encroaching fat is not found on the jejunum but on the ileum.
    • Circular folds (plicae circulares) are large, tall & closely packed in the jejunum but low & sparse in the ileum.
    • The ileum has aggregated lymphoid nodules (Peyer’s patches).
  36. Features of large intestine
    • Teniae coli: 3 thickened bands of muscle
    • Haustra: sacculations
    • Epiploic appendices: fat
  37. Hindgut
    • Distal 1/3 of transverse colon to anus
    • Lumbar splanchnic (symp T12-L2) Pelvic splanchnics (parasymp)
  38. Anal canal
    • external anal sphincter: deep, superficial & subcutaneous part
    • anal canal: columnar zone (endoderm derived), anal pectin (transitional zone) & cutaneous zone (ectoderm derived).
    • Puborectalis muscle keeps an 80 deg anorectal flexure
  39. Portal triad and direction of flow in liver
    • bile duct, hepatic artery, portal vein, lymph
    • hexagon: blood flows from traid -> central vein, bile flow opposite
    • zone 1 - at triad, high O2 & gluconeogenesis
    • zone 3 - at CV, low O2, liponeogenesis
  40. Blood supply to liver
    • Portal vein - 70%
    • Hepatic artery - 30%
    • Fenestrated endothelium
    • 1/3-1/2 can be regenerated
    • splanchnic capillaries & liver sinusoids = portal system
  41. pre-sinusoidal portal hypertension
    • Portal vein thrombosis
    • Schistosomiasis
  42. post-sinusoidal portal hypertension
    • Venoocclusive disease
    • Budd Chiari
    • IVC Web
    • Heart failure
  43. where is the apical membrane in the liver?
    • apical - between cells, where bile is secreted into canniculi
    • basolateral - adj to sinusoids
  44. vitamins lost in diarrhea
  45. Fat soluble vitamins A,D,E,K and water soluble vitamin B12 lost
  46. Composition of bile
    67 % Bile Salts

    • 26 % Phospholipids
    • (lecithin) and cholesterol

    4.5 % Proteins

    0.3 % Bilirubin
  47. functions of bile
    • 1.Form mixed micelles (hydrophobic core) with fatty acids and monoglycerides for cholesterol transport
    • 2.Solubilize “fatty” vitamins A,D,E, and K to promote their absorption
    • 3.Promote the absorption of heavy metals (Fe++)
    • 4.Keep intestinal surface clean
    • 5.May promote intestinal motility
    • 6.Mild bacteriostatic effects
    • 7.In colon they induce water secretion and stimulate colonic motility
  48. What puts you at risk for gallstones?
    Bile with > 10% cholesterol tends to form cholesterol crystals and then gallstones

    • 1.Increasing age
    • 2.Female > male
    • 3.Obesity
    • 4.Hemolytic anemia (pigment stones)
    • 5.Pregnancy
    • 6.Estrogens
    • 7.Total parenteral nutrition (TPN)
    • 8.Fasting
    • 9.Ethnicity (Pima)
    • 10. Diabetes
    • 11. Cirrhosis
    • 12. Terminal ileal disease (IBD)
    • …think about disruption of the enterohepatic circulation!
  49. Consquences of cholestasis
    • 1. Cholelithiasis (Gallstones)
    • 2. Jaundice
    • 3. Pruritus
    • 4. Darkening of urine (bilirubin spilling into urine)
    • 5. Malabsorption (A,D,E,K)
    • 6. Steatorrhea
    • 7. Pain (epigastric, RUQ, right shoulder)
    • 8. Hepatotoxicity (untamed bile acids are highly toxic)
    • 9. Kernicterus (neonates)
  50. Cholestasis treatment
    • • Remove the obstruction
    • • Remove the offending agent
    • • Treat the underlying condition (sepsis, PBC)
    • • Lower cholesterol (DM, hyperlipidemia)
    • • Ursodiol: Partially inhibits cholesterol synthesis (HMG-CoA reductase) inhibition; Stabilizes canalicular membrane; Solubilizes cholesterol and improves biliary flow; “dissolves stones”
  51. Pathway of bilirubin metabolism
    • macrophages: heme->bilirubin&biliverdin
    • plasma: unsoluble bili binds to albumin
    • liver: bili separates from albumin, is taken up, conjugated w/glucoronic acid
    • bile: conj. bili -> urobilogen in intestine
    • @ high levels, urobilogen is reabsorbed and excreted in urine
  52. Uptake of Fe3+ from diet
    • heme taken up into enterocytes
    • transporter converts Fe3+ to Fe2+
    • Stored in ferritin (apo) - some leaks into plasma, can judge Fe levels by this
    • Apoferritin synth inhibited when Fe levels are low
    • Converted back into Fe2+ at basolateral membrane
  53. hemochromatosis
    • excessive absorption of Fe
    • mutation of HFE or hepcidin genes
    • in the fetus, hepcidin regulates transport of Fe by ferroportin
    • bronze skin, damaged liver, heart, pancreas
  54. anemia of chronic disease
    • hecipidin induced by cytokines
    • normally produced by liver
    • binds to ferroportin
    • causes macrophages to accumulate Fe
    • MCV is not as low as in anemia of Fe deficiency because high hepcidin will prevent nascent RBCs from exporting Fe to restore plasma Fe levels
  55. sideroblastic anemia
    • Fe accumulation in erythroblasts
    • Excess ferritin can precipitate to form“hemosiderin”
    • Hereditary defect in heme synth or acquired (lead poisoning)
  56. porphyrias: acute
    • defects in heme synthesis
    • acute: earlier steps (ALA)
    • cutaneous: later steps, sun lesions, red teeth, urine
  57. Cimetidine
    • H2 receptor antagonist
    • antacid
    • inhibits many CYP450s
    • SE: diarrhea, dizziness, headache, rash, confusion
  58. erthyromycin
    • antibiotic/motilin agonist
    • binds to 50s bacterial
    • SE: GI upset
  59. Fluoxetine
    • SSRI antidepressant
    • GI discomfort, diarrhea, nervousness, anxiety, nausea
  60. Metoclopramide
    • 5HT3 antagonist, 5HT4 agonist
    • D2 antagonist
    • prokinetic drug (antiemitic)
    • treats reflux esophagitis
    • SE: diarrhea, drowsiness, depression
  61. Misoprostol
    • PG E1 analog
    • prevents gastric ulcers
    • mucus and bicarb secretion
    • SE: diarrhea, dyspepsia, abd pain
  62. neostigmine
    • carbamate-type AChEI
    • increases bladder tone, gastric motility, treats myasthenia gravis
    • SE: bowel cramps, diarrhea
  63. Octreotide
    • somatostatin analog
    • treats diarrhea, orthostatic hypotension, variceal bleeding
    • inhibits gastrin/pepsinogen secretion
    • reduces motility, gallbladder contractions
    • SE: cramps and nausea
  64. hepcidin
    • inhibits Fe release from macrophages by binding ferroportin
    • high levels of ferritin intracellular -> high [ferritin] plasma also
    • apoferritin synth inhibited by low intracellular Fe3+
    • defect secondary to chronic disease
  65. Sources of NH4+
    • glutaminase in kidney
    • aminotransferases
    • bacterial digestion
    • catabolism of catecholamines and nucleotides
  66. urea cycle
    • urea exreted by kidney 75%, intestine 25%
    • arginine increases excretion (allows regeneration of ornithine and synthesis of arginosuccinate, which is efficiently excreted by the kidney)
    • Sodium benzoate, sodium phenylacetate
  67. acquired hyperammonemia
    • shunts secondary to portal hypertension cause NH3 absorbed from GI to bypass the liver
    • decreased urea synthesis due to damaged hepatocytes
    • toxicity due to: increased synth of glutamate, lack of alpha-KG, lack of ATP, hepatic encephalopathy
  68. EtOH abuse
    • disulfiram
    • consumes NADPH, which is needed to power glutathione reductase to regenerate GSH
    • GSH keeps Hb Fe in ferrous state
    • Anti-oxidant
  69. action of aspirin v. clopidegrel
    • aspirin - inhibits synth of thromboxane A2
    • clopidegrel - blocks binding of ADP to receptor on platelet
  70. Intrinsic pathway
    • activated in vitro by interaction of factor XII, kininogen and kallikrein with the damaged surface of container
    • activation process is not important in vivo because factor XII, kininogen and kallikrein are not required in vivo
  71. thrombin
    • Cleaves fibrinogen to fibrin
    • Cleave a thrombin receptor on platelets to activate platelets (second pathway of platelet activation)
    • Cleave V and VIII to from active Va and VIIIa
    • Limit clot formation by eventually cleaving Va and VIIIa
  72. limiting clot formation
    • Protein C activated by thrombin complex + Protein S -> cleaves Va, VIIIa
    • antithrombin + active protease -> inactive complex (heparin increases the activity of antithrombin)
  73. dissolution of clot
    • TPA = tissue plasminogen activator
    • plasminogen-TPA->plasmin
    • plasmin breaks down fibrin clot