GASTROINTESTINAL PHYSIOLOGY. Smooth muscle: All smooth muscle is innervated by the autonomic nervous system.

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1 GASTROINTESTINAL PHYSIOLOGY ENTERIC NERVOUS SYSTEM Smth muscle: All smth muscle is innervated by the autnmic nervus system. General Prperties: Cavelae: Micr-pits allw fr increased surface area n smth muscle. N Striatins: Thin and thick filaments run thrugh in a randm rder. Smth muscle has relatively mre thin filaments than thick. Plasticity: Smth muscle is able t stretch t a greater length and cmpress t a shrter length than skeletal. Calcium supply cmes mre frm utside the cell rather than inside (in the SR), as cmpared t skeletal. Slw, Sustained cntractin as cmpared t skeletal muscle. Multi-unit smth muscle: Has high innervatin density. This is the type f smth muscle fund in Ciliary Muscle and Ductus Deferens. UNITARY SMOOTH MUSCLE: The type f smth muscle fund in gut. Sparse innervatin cmpared t multi-unit muscle Functinal Syncytium: Gap junctins allw intercellular cmmunicatin. Shws spntaneus (basal) electrical activity even in the absence f innervatin. High basal resting ptential (-57 mv -vs- -80 mv) as cmpared t skeletal muscle. Smth muscle is mre permeable t Na + which accunts fr spntaneus electrical activity. SMOOTH MUSCLE CHANNELS: Electrmechanical Channels: Channels that transduce electrical activity, in ne frm r anther, t mechanical activity f actin and mysin. Slw-Leaking Ca +2 -Channels Ligand-Gated Channels Vltage-Gated Na + -Channels Pharmac-mechanical Channels: Channels that emply a secnd messenger, causing cntractility withut a change in the cell's electrical ptential. SMOOTH MUSCLE CONTRACTION: Ca +2 enters cell > Calmdulin then activates Mysin Light-Chain Kinase (MLCK) > MLCK then phsphrylates mysin, turning it n and enabling it t interact with actin > cntractin ccurs. Regulatry step is binding f Ca +2 with Calmdulin. SLOW-WAVES: The basal electrical tne f smth muscle. N cntractin ccurs with slw-waves. Als called the Basal Electrical Rhythm (BER) Magnitude f change is 5-15 mv, caused by entrance f Na + int cell. N Ca +2 is assciated with these waves s n cntractin ccurs with them. Basal Rhythm in Different Regins: Remember these waves are nly electrical -- nt mechanical. STOMACH: 3 waves per minute DUODENUM: 12 waves per minute. In the dudenum, 30-40% f slw-waves are assciated with Ca +2 as Ca +2 is added t the cells. ENTERIC NERVOUS SYSTEM: The GI nervus system is independent f the CNS. Activity can g n withut any CNS input. GI Plexes: MYENTERIC PLEXUS: Outermst plexus lcated between the tw layers f musculature -- between the muscularis circularis and muscularis lngitudinalis. SUBMUCOSAL PLEXUS: Lcated in the submucsa, just utside the Muscularis Mucsae. EXTRINSIC REGULATORY INPUT: Chemreceptrs and mechanreceptrs frm the GI-Lumen are an imprtant surce f input. They are the rigin f shrt reflexes (nt invlving the CNS) that g thrugh the tw GI plexes in the enteric NS. 1

2 VAGO-VAGAL (lng) REFLEX: Generally stimulatry (increase mtility, secretmtr, vasdilatry). The Vagus carries bth afferents (70%!) and efferents. Luminal receptrs send afferent signal back t the CNS via the Vagus. INTESTINO-INTESTINAL (shrt) REFLEX: Generally inhibitry, invlving nly the Enteric NS, and cmpletely independent f the Autnmic NS. SYMPATHETICS are inhibitry t the GI-Tract. They wrk primarily by presynaptic inhibitin, thus inhibiting release f ACh. In this way we get smth muscle relaxatin. Nrepinephrine binds t alpha1-adrenreceptrs n parasympathetic nerve terminals and thereby inhibit the release f ACh. NEUROTRANSMITTERS: Acetylchline increases GI-Mtility when it acts n smth muscle. Nrepinephrine decreases GI-Mtility when it acts n smth muscle. Enkephalin (Opiid) decreases GI-mtility by inhibiting the release f ACh. VASOACTIVE INTESTINAL PEPTIDE (VIP): Acts directly n smth muscle t cause smth muscle relaxatin. It is lcalized with ACh in the Vagus Nerve. VIP is in lcal neurns, and is released when Vagal Fibers excite these inhibitry neurns t cause relaxatin: Vagus (Excitatry synapse) > Turn n VIP neurns (Inhibitry synapse) > Relaxatin. COLOCALIZATION: Enkephalins, VIP, NO, Sertnin, and a whle bunch f ther transmitters are lcalized alng with ACh and NrE in the autnmic nervus system. Depending n the nerve, whenever the ACh and NrE are released, s will the ther substances be released. MYOGENIC CONTRACTILITY: The gut has sme cntractility withut any nervus input whatsever. Luminal cntents will cause basal cntractility withut any nervus influence at all. Thus there is a cnstant inhibitry tne f VIP and NO n the gut, t prevent / slw dwn this cntractility. PARALYTIC ILEUS: Lss f GI cntractility. It can ccur chrnically frm verprductin f Sympathetics. Pst-Operative (Physilgic) Ileus is a very cmmn ccurrence with abdminal surgeries TYPES OF MOTILITY: PERISTALSIS: Prpulsin f material in the abral (away frm muth) directin. Rate f peristalsis varies in regin, but peristaltic generally gets slwer as we mve dwn the tract. Peristalsis ccurs by segmental hyperplarizatin fllwed by deplarizatin f muscle. Mechanism: Blus f fd in a particular lcatin stimulates mechanreceptrs and chemreceptrs in the GI lumen, ultimately resulting in peristalsis: Relaxatin f the muscle ccurs distal t the blus, s that the fd can g frward. This is mediated by VIP / NO. Cntractin f Lngitudinal Muscle layer als ccurs distal t blus, because lngitudinal cntractin causes widening f the GI lumen. Cntractin f the muscle ccurs prximal t the blus, in rder t prpel the blus frward. There is a basal level f VIP inhibitin in the muscle, and a blus f fd turns ff this inhibitin: distensin f lumen by a blus will cause inhibitin f release f VIP / NO > cntractin f prximal regin. RHYTHMIC SEGMENTATION: Mixing and churning f materials withut prpelling them frward in the tract. Only invlved the circular muscle -- nt lngitudinal Cmmn in small and large intestine TONIC CONTRACTION: Blcking f the passage f material, as in sphincters. Tnic Cntractin is mygenic -- it desn't depend n innervatin. 2

3 HORMONES, ENZYMES, REGULATORY SUBSTANCES AND STUFF NEUROENDOCRINE HORMONES: All f belw are either exclusively endcrine (glandular secretins int bldstream), exclusively neural (neurtransmitter) r bth. All f belw serve regulatry (as ppsed t digestive) functins. GASTRIN: Endcrine. STRUCTURE: Active part f peptide is n carbxy-end. It shares the last fur residues in cmmn with CCK (Trp-Met-Asp-Phe), and it has a prtective NH 2 n the carby end t help prevent degradatin. PENTAGASTRIN Drug that mimics Gastrin, cntaining the last fur residues in gastrin, and therefre cntaining similar bilgical activity. Distributin: Gastrin is made by G-CELLS in the ANTRUM f the Stmach. FNXNS: It stimulates release f HCl in Parietal Cells. Als stimulates grwth f gastric mucsa and prliferatin f intestinal entercytes. Intestinal Resectin: If yu cut ut part f the intestine, higher levels f Gastrin will result. REGULATION: Gastrin release is inhibited by acid in the stmach. Primary negative feedback mechanism. Gastrin release is stimulated by digested prteins and by Acetylchline. CHOLECYSTOKININ (CCK): Endcrine and neural STRUCTURE: Bilgical activity is cntained in last seven residues n carbxy-end, with last fur residues in cmmn with Gastrin, and with a prtective NH 2 n the carbxy terminus. Activity n PARIETAL CELLS: CCK in the stmach can bind t Gastrin receptrs t BLOCK the effects f Gastrin. Distributin: CCK is made frm I-CELLS FNXNS: Stimulates cntractin f the gall bladder Stimulates secretin f pancreatic enzymes. Inhibits gastric emptying as part f the Enter-Gastric Reflex. The presence f CCK indicates that the dudenum is currently full and gastric emptying shuld be slwed. REGULATION: CCK-release is stimulated by the presence f peptides in the dudenum. SECRETIN: Endcrine and neural Distributin: Secretin cmes frm S-CELLS in the dudenum. FNXNS: It inhibits stmach mtility when released in Dudenum bia the Enter-Gastric Reflex. REGULATION: Secretin-release is stimulated by acid in the Dudenum. SOMATOSTATIN: The universal inhibitry substance. It acts in endcrine, neural, and paracrine fashin. Distributin: Smatstatin is all ver the place. GASTRIC INHIBITORY PEPTIDE (GIP): Endcrine. FNXNS: Inhibits the release f Gastrin by a pharmaclgical mechanism. Thus the effect is dsedependent, and a large (nn-physilgical) dse is required t elicit a respnse. Dr. Greenwald thinks this effect is secndary imprtance because it is nly pharmaclgical. Majr fnxn = GIP stimulates release f Insulin frm Pancreas DISTRIBUTION: Antrum f stmach + dudenum. VASOACTIVE INTESTINAL PEPTIDE (VIP): Primarily neural MOTILIN: Endcrine. FNXN: It elicits the Migrating Mtr Cmplex in the small intestine, t prpel bacteria abrally. GASTRIC RELEASING PEPTIDE (GRP) (Bmbesin): Neural. Invlved in the release f Gastrin. Its release is Nn-Adrenergic Nn-Chlinergic. REGULATION: Its release stimulated during the Cephalic Phase f gastric secretin. ENKEPHALIN (an Opiid): FNXN: Decreases GI-mtility by inhibiting the release f ACh. 3

4 PREGNANCY: Pregnant wmen tend t gain weight because they have increased levels f CCK (higher fat and prtein absrptin) and lwer levels f Smatstatin. Higher CCK is especially marked during first trimester. INFANTS have very high levels f Gastrin t accmpany their very high calrie-per-bdy-weight intake. Gastrin interacts with hypthalamus t smehw prmte anablic grwth in infants. MOTILITY THE ESOPHAGUS: Anatmy and Pressures: Upper Esphageal Sphincter (UES): Skeletal muscle, essentially cmprising the cricpharyngeus muscle. Resting pressure = mm Hg t prevent swallwing f air. Muscle tne is neurgenic and depends n CNS neural input frm swallwing center t remain active. Bdy: Cmbinatin f skeletal and smth muscle. Resting pressure = -5 mm Hg Lwer Esphageal Sphincter: Smth muscle, nrmally clsed in rder t prevent gastric reflux. Resting pressure = 30 mm Hg LES cntractility is mygenic. The way we relax the LES is by putting tnal amunts f VIP / NO n the sphincter. VIP inhibitin f LES is Nn-Adrenergic, Nn-Chlinergic (NANC). We knw this because Atrpine des nt prevent the inhibitin: Give atrpine, and the LES will still relax because VIP is nt stpped. Give a VIP-Antibdy and the LES will n lnger relax because inhibitin has been remved. SWALLOWING REFLEX: Can be studied with Manmetry (esphageal pressure) studies. Oral Phase: 1 secnd, vluntary. Pharyngeal Phase: 1 secnd, invluntary. It is stimulated by the presence f the slightest fd r liquid (saliva) in the back f the thrat. Yu cannt swallw if yur muth is abslutely dry. Aspiratin f fd is prevented: Respiratin is inhibited frm this pint frward. Epiglttis is NOT imprtant in preventing aspiratin. Rather it is adductin vcal crds that prevents fd getting int trachea.. Esphageal Phase: 8-10 secnd, invluntary Esphageal Peristalsis Esphageal Peristalsis is a Vag-Vagal (CNS mediated) Reflex. RELAXATION f Lwer Esphageal Sphincter ccurs early in the swallwing reflex -- befre the end f peristalsis f the esphagus. At the end f swallwing the LES shuld tighten up again t prevent reflux f gastric cntents. Types f peristalsis: PRIMARY PERISTALSIS: The initial peristalsis, initiated by the swallwing reflex. SECONDARY PERISTALSIS: Any subsequent peristalsis, t get any remaining fd ut f the esphagus. It is initiated by distensin f esphagus and mechanreceptrs n smth muscle. The UES des NOT pen with secndary peristalsis. It desn't need t pen. ACHALASIA: Tnic high pressure at the LES, making it difficult t swallw. Failure f LES t relax due t lack f VIP r because enteric system has been kncked ut. ETIOLOGY: Culd be caused by sympathetic ver expressin (Sympathetics will cause relaxatin via stimulatin f VIP neurns) r by VIP under expressin. SYMPTOMS: Distended esphagus because fd can't easily get t stmach. Lacking r uncrdinated peristalsis; r n peristalsis at all. Spastic uncrdinated cntractins fllwing meal. 4

5 GASTRO-ESOPHAGEAL REFLUX DISEASE (GERD): Having an incmpetent r ver-relaxed LES. Heartburn. Newbrn babies dn't have a cmpetent LES, hence they burp up fd a lt. Secndary peristalsis can help alleviate the symptms by pushing unwanted chyme back int the stmach. Esphagitis and Esphageal Cancer can result frm chrnic cases. Lying dwn after a meal (i.e. lack f gravity) wrsens the reflux. PROPULSID = drug that causes cntractins f the LES, hence a treatment fr GERD. It acts n ACh receptrs t amplify the effect f ACh. THE STOMACH: FNXNS: RECEPTIVE RELAXATION: The stmach is a reservir f fd and can accmmdate large changes in vlume. Pressure increase with mre fd is gradual. Mechanism: Vag-Vagal. Mre fd > distend stmach wall and activate mechanreceptrs > mre VIP n stmach wall > relaxatin. It cnverts fd t chyme. It cntrls the rate f Gastric Emptying, s dudenum desn't get verladed with blus. BASAL ELECTRIC RATE: Stmach BER is abut 3 events per minute. This number represents the maximum number f cntractins that can ccur per minute. GASTRIC EMPTYING: The rate f mvement f fd frm the antrum f the stmach, thrugh the Pylric Sphincter (a true sphincter), and int the dudenum. General Prperties: Retrpulsin: Stmach cntractins riginating at antrum and ging backward, t prevent t rapid f gastric emptying. Liquids empty befre slids. Fats are slwest emptying f all substances. CHO's and prteins empty first. Istnic cntents empty befre hyptnic cntents. Stmach acid impedes the rate f gastric emptying. ENTERO-GASTRIC REFLEX: Negative feedback frm dudenum will slw dwn the rate f gastric emptying, by multiple mechanisms. Basically, whenever there is fd in the dudenum, gastric emptying will be dwn-regulated. Acid in dudenum > stimulate Secretin release > inhibit stmach mtility via Gastrin inhibitin Fats in dudenum > stimulate CCK and GIP > inhibit stmach mtility Hypertnicity in dudenum > (unknwn hrmne) > inhibit gastric emptying. ABNORMAL EMPTYING: The majr rle f the dudenum is t restre istnicity. Dumping (Gastric Emptying) Syndrme = TOO RAPID emptying, which can result frm resectin f part f the stmach SYMPTOM: T rapid emptying > hypertnic blus in dudenum > pull fluid in frm circulatin > Severe cardiac prblems and hypvlemia. DELAYED EMPTYING can ccur frm diabetic neurpathy. It can cause nausea, heartburn, and reflux. SMALL INTESTINE: Basal Electrical Rate: Fastest is in dudenum (12 cycles / min). It gets increasingly slwer as yu mve thrugh intestine. LAW OF THE INTESTINE: The decreasing electrical rate as yu mve thrugh tract is ultimately respnsible fr the mvement f fd in an abral (i.e. frward) directin. The general mvement f fd abrally is a result f the basal electrical rate. MYOGENIC: Small intestinal mtility is mygenic. If yu give tetrdtxin t kill all the nerves, yu still get mtility. ILEOCECAL SPHINCTER: Smth muscle sphincter which acts by shrt (intestin-intestinal) reflexes. Atrpine has n effect n it. Distensin n ileal side f sphincter > sphincteral relaxatin > blus can pass thrugh. 5

6 Distensin n clnic side f sphincter > sphincteral cntractin > blus is prevented frm mving backward. COLON: Basal Electrical Rate: The cln has the slwest f all BER's. HAUSTRATIONS: Slw segmental mvements that mve fd very slwly thrugh cln. This mvement is ging n cntinually. Mass Mvements result frm GASTRO-COLIC REFLEX: Fd entering int stmach can cause much mre rapid and frceful peristalsis in cln, ultimately resulting in defecatin. This phenmenn will esp. happen in the mrning. ANAL SPHINCTER: Internal Anal Sphincter is smth and external anal sphincter is skeletal. As yu increase pressure in rectum (distend it), tw things happen: The Internal Anal Sphincter relaxes t accmmdate the fecal matter. The External Anal Sphincter cntracts t prevent defecatin. Pping is vluntary (usually). FIBER is fd that is nt digested nr digestible. A large cnstituent f fiber is cellulse which human can't digest. Fiber lwers bwel transit time, especially thrugh the cln. MIGRATING MOTOR COMPLEX (MMC): Husekeeping functin thrughut the small intestine, t sweep bacteria abrally. The MMC ccurs pst-prandially, after a meal. MMC is caused by Mtilin and Acetylchline -- it is blcked by atrpine. VOMITING: VOMITING (EMETIC) CENTER: In the medulla. The fllwing receptrs feed int the vmiting center. Chemical Trigger Zne: Flr f the furth ventricle, cntrlled by higher centers. Apmrphine is a drug that stimulates the chemical trigger zne. Labyrinthine Receptrs in the inner ear, effected by balance. Tuch Receptrs in thrat (as in gagging reflex) Mechanreceptrs and Chemreceptrs in stmach and dudenum. RETCHING AREA: That regin f the brain respnsible fr the act f retching (reverse peristalsis). OUTPUT: The vmiting act. Fur muscle grups are stimulated in synchrnus rder t prduce vmiting. Fur grups f muscles are stimulated: this is the prcess f retching, which is reverse peristalsis accmpanied by relaxatin f esphageal sphincters. Inspiratry Muscles: Deep inspiratin > negative thracic pressure t facilitate upchucking. Abdminal Muscles > psitive intraabdminal pressure t facilitate upchucking. Esphageal, gastric, and dudenal muscles all underg reverse peristalsis. Esphageal sphincter (LES and UES) must relax fr vmiting t ccur. Massive Autnmic Discharge ccurs with vmiting. cmbined sympathetic / parasympathetic n salivary glands causes hypersalivatin SECRETIONS and ABSORPTION SALIVARY SECRETIONS: Average abut 1500 ml a day. Secreted Substances: Majr functin f saliva is prtectin and digestin. Salivary Amylase: Secreted primarily by Partid gland. Amylase nrmally perates at ph 7-8 and is therefre inactivated nce in the stmach. Hwever, if it is inside a blus f fd and prtected n all sides then it can still be active even in stmach. Mucus: Secreted by the ther glands (Mandibular and sublingual). FNXN: Lubricatin f fd and it serves as a buffer. Lactferrin: Binds Fe in muth, preventing bacteria frm getting it. It thereby serves as an antibacterial rle. 6

7 Lingual Lipase: Released frm tngue itself, allws easy mvement f fats n the tngue. It can serve a backup functin in case pancreatic lipase is lacking. Secretry IgA: Antibacterial secretins. Lyszymes: Antibacterial secretins. XEROSTOMIA: Dry muth. It can lead t caries (cavities) because the anti-bacterial salivary secretins are lacking. It als leads t impaired speech because saliva is required fr speech. HYPOTONICITY: Salivary secretins are hyptnic and cncentrated in HCO - 3 and K +, due t exchangers in the salivary ducts. - High in HCO 3 and lw in Cl -, giving basic ph, frm a HCO - 3 /Cl - exchanger in salivary ducts. Lw in Na + and higher in K +, as a result f a Na + /K + -ATPase exchanger in salivary ducts. The salivary ducts are impermeable t water, s they retain fluid which results in hyptnicity. Nervus Stimulatin f Salivatin: Bth sympathetic and parasympathetic cause salivatin, but parasympathetic is the primary ne. Increased salivatin generally results frm vasdilatin > increased bld flw t salivary glands. GASTRIC SECRETIONS: Parasympathetic: Tw pathways Chlinergic Pathway causes vasdilatin via tw mediatrs: It causes prductin f kallikrein (a vasdilatr) and it causes cnversin f Plasma Kiningen > Bradykinin (anther vasdilatr). VIP Pathway causes vasdilatin directly n the vascular bed. GASTRIC EPITHELIAL CELL TYPES: Parietal Cells: Prduce HCl G-Cells: Prduce Gastrin. Mucus Neck Cells (alng the length f the villus): Prduce sluble mucus Chief cells: Prduce pepsingen Surface Mucus Cells: Prduces insluble mucus, which secretes HCO - 3 which serves as a ph-buffer fr the mucsa -- especially in stmach. Stem Cells in crypt PARIETAL (OXYNTIC) CELLS: Prduce gastric acid. Stmach ph 1.3 Carbnic Anhydrase: Parietal cell creates carbnic acid via this enzyme: CO 2 + H 2 O <====> H 2 CO 3 <====> HCO H + The H + is then secreted int the lumen. ALKALINE TIDE: The HCO - 3 is transprted int the prtal circulatin and ges t the dudenum. Transprt ccurs by a HCO - 3 /Cl - antiprt. The Cl - then cmes in and ges t the lumen where it jins the H + t frm HCl. PARIETAL CELL STIMULATION: Three things stimulate parietal cells in synergy -- the effects are additive, but the effect f all f them tgether is greater than the sum f the individual effects. Histamine: H2-Receptrs are cupled t a G-Prtein and act via the beta-adrenergic (camp) pathway. H 2 -Blckers blck the histamine receptr. There is an H 1 -Receptr fr histamine in the lungs, which mediates lung mucus secretins. Acetylchline: Muscarinic receptr that acts by the alpha-adrenergic pathway (IP 3 ) Atrpine blcks the ACh receptr, duh?? Gastrin: Gastrin als acts by the alpha-adrenergic pathway (IP 3 ). Prglutamide blcks the gastrin receptr. CCK will blck the gastrin receptr. H + /K + -ATPase symprt brings the H + int the cell. K + gradient is maintained by the traditinal Na + /K + - ATPase. OMEPRAZOLE blcks the H + /K + -ATPase. Gd drug fr antacid. PHASES OF GASTRIC SECRETION: BASAL PHASE: 15% f secretin. CEPHALIC PHASE: 30% f secretin, ccurs when fd is seen, smelled, r tasted. Stimulus riginates frm higher centers (hence "cephalic"). Vagus Nerves releases Acetylchline during this phase. ACh has tw effects: Stimulates release f Gastrin frm G-Cells 7

8 Inhibits Smatstatin release frm enterendcrine. Gastric Releasing Peptide is als released in stmach. This release is Nn-Adrenergic Nn- Chlinergic. It als stimulates release f Gastrin. GASTRIC PHASE: When fd enters stmach, abut 50% f secretin. INTESTINAL PHASE: Pst-gastric-emptying. NEGATIVE FEEDBACK: ACID is the primary inhibitr f Gastric secretins. Acid stimulates the release f Smatstatin, which turns ff Parietal Cells and G-Cells. GASTRIC MUCOSAL ISCHEMIA: Ischemia f mucsa causes increased permeability > Gastric Ulcers Etilgy: Lts f things; shck, burns, sepsis, trauma. Treatment: Use acid-reducers like H 2 -Blckers VICIOUS CYCLE: The excess acid can cause cnversin f pepsingen t pepsin which will stimulate further acid release. That nrmally nly ccurs in lumen but with a lesin it can ccur in mucsa, and that is nt gd. HELICOBACTER PYLORI: Thse little critters in the stmach that have been recently prven t cause ulcers. Urease: These bacteria can survive in acid because they have high urease which can take urea and create HCO - 3 and NH 3 ut f it, frming a gd acid-buffer. ULCER treatment shuld include antibitics t fight these bacteria, but H.Pylri is nt always fund in ulcer patients! Criteria fr determine presence f H-Pylri: D a bipsy and identify histlgically Grw cells in culture Measure the amunt f the enzyme urease. INTRINSIC FACTOR (IF): Prduces by parietal cells in stmach, it is necessary fr Vit-B12 absrptin. Saliva: Vit-B12 cmbines with R-Prtein. Stmach: Secretes intrinsic factr int blus. Intestine: Vit-B12 lets g f R-Prtein and binds t Intrinsic Factr Ileum: The Vit-B12/IF Cmplex is absrbed thrugh special transprters. Withut the IF, nly 20% f B12 is absrbed. PERNICIOUS ANEMIA: Autimmune disease destrys parietal cells, thereby destrying intrinsic factr surce and resulting in B12-deficiency. ACHLORHYDIA is an vergrwth f bacteria in stmach resulting in lw HCl secretin which will cause high Gastrin levels. PEPSIN: Released as pepsingen in chief cells. Acid cnverts the prenzyme t pepsin. Pepsin is an endpeptidase. Pepsin can cntinue t activate itself nce active. REGULATION: Fllwing factrs stimulate pepsingen secretin, frm mst t least prminent. Acetylchline H + Secretin CCK Pepsingen I fund in Chief Cells. Pepsingen II fund in dudenum and crrelates with dudenal ulcers. ZOLLINGER-ELLISON SYNDROME: ETIOLOGY: Pancreatic tumr > Under secretin f Pancreatic Enzymes > Over secretin f GASTRIN due t n CCK. SYMPTOMS: Peptic Ulcer Disease Increased Gastric Emptying. Diarrhea frm hypergastrinemia Steatrrhea (fat in stl): Denaturatin f pancreatic lipase due t acidic envirnment in the dudenum. Reduced Intrinsic Factr activity. GERD 8

9 PANCREATIC SECRETIONS: General Prperties: They are basic (ph = 8.2). Higher HCO - 3 at increased flw levels until it plateaus. They are istnic (unlike salivary hyptnic) REGULATION: Secretin and CCK bth stimulate pancreatic secretins. H > stimulates S-Cells t secrete Secretin > stimulates pancreatic enzymes. Fats in dudenum > stimulate I-Cells t secrete CCK > stimulates pancreatic enzymes. BOTH CCK and Secretin are required fr maximal (r near maximal) pancreatic secretin. - Phenylalanine stimulates the release f CCK, and it cupled with Secretin results in maximal HCO 3 secretin frm pancreas. ACID TIDE: Pancreatic Ductal Cells cunter the alkaline tide with an acid tide. Na + /H + Antiprt transprts H + int the bld (which cunteracts the HC - 3 frm parietal cells). Carbnic Anhydrase can then make lts f HCO - 3, which it secretes int the lumen. GALL BLADDER / BILIARY SECRETIONS: Gall Bladder cncentrates Bile frm the liver. NaCl is pulled ut f gall-bladder cells, and H 2 O fllws, s that bile becmes supercncentrated. CHOLAGOGUE: Any substance that causes cntractin f the gall bladder, such as CCK. CHOLERETIC: Any substance that increases the flw f bile dwn the bile duct, but des nt affect bile synthesis. Example = bile salts. HYDROCHOLERETIC: Any cmpund that prmtes the secretin (synthesis) f bile in the liver, such as Secretin. Sphincter f Oddi keeps the bile in the gall bladder. It is tnically cntracted when n fd is in the dudenum. CCK causes cntractin f the gall bladder and relaxatin f the Sphincter f Oddi. MICELLES: Bile Salts + Chlesterl + Lecithin LECITHIN (PHOSPHATIDYLCHOLINE): MICELLES require lecithin t functin at maximum efficiency. It increases threefld the fat-emulsifying capacity f micelles. SYNTHESIS / STRUCTURE OF BILE ACIDS: Bile acids are synthesized frm chlesterl in the liver, stred in the gall bladder, and secreted thrugh the cmmn bile duct. SYNTHESIS f BILE ACIDS: 7alpha-Hydrxylatin f Chlesterl: The key, rate-limiting step in bile-acid synthesis. This hydrxylatin destines the prduct t becme a bile-acid. CHOLATE: The majr bile acid. It has three OH-grups in the rings, and a carbxylic acid at the end f the side chain. It is mre amphipathic than dexychlate because it has ne mre hydrxy grup. DEOXYCHOLATE: The minr bile acid. It is missing ne f the OH-grups (at the 12 carbn) REGULATION f BILE SYNTHESIS: Negative Feedback frm the Bile Acids themselves. They inhibit 7alpha- Hydrxylase. SYNTHESIS OF BILE SALTS: LIVER -- Bile Acids esterified t Glycine r Taurine. Bile Salts are even mre plar than their crrespnding acids. Glycchlate: Chlate with glycine added as an amide functin. Taurchlate: Chlate with Taurine added as an amide functin. Taurinine is a mdified cysteine. Glycchendexychlate and Taurchendexychlate are the minr bile salts. SECONDARY BILE ACIDS AND SALTS: Bacteria in the INTESTINE mdify bile salts by remving the 7alphacarbn, t the "secndary" bile salts. ENTEROHEPATIC CIRCULATION: The circulatin f bile between the intestine and liver. New Synthesis: A small f bile acids are newly synthesized every day. This is mixed in with bile acids that are recirculated. Cnjugatin: Adding the glycine r taurine t the bile acid t frm a bile-salt, befre secretin. This ccurs in the liver. Secretin: We secrete daily abut grams f bile acids int the GI tract. Decnjugatin: Decnjugatin and reductin f bile salts ften ccurs in the intestine, aided by intestinal bacteria. 9

10 Reabsrptin: 90% f the bile acids are reabsrbed in the intestinal tract -- in the ileum, after mst nutrients have already been absrbed. Reabsrptin sends the acids thrugh the prtal circulatin and ultimately back t the liver. Excretin: Sme bile acids are excreted in the feces n a daily basis, abut the same as the amunt that is newly synthesized every day. This is ne way t get rid f chlesterl. GALLSTONES ccur when bile is cmpsed f mre than 15% chlesterl. This makes chlesterl precipitate ut f the bile slutin and frm stnes. WOMEN are at higher risk fr gall stnes because estrgen tends t yield higher chlesterl levels. Wmen taking BIRTH CONTROL are at even higher risk, relatively, fr same reasn. BILIRUBIN METABOLISM AND EXCRETION: Bilirubin is the nrmal prduct f heme-breakdwn. It is carried by Albumin in the bld stream, where it ges t liver. LIVER: Bilirubin is cnjugated t Bilirubin Glucurnide, making it water sluble and lipid insluble. Bilirubin Glucurnide is then secreted in bile t intestine. INTESTINE: Bilirubin Glucurnide is cnverted t Urbilingen by stepwise reductins mediated by intestinal bacteria. UROBILINOGEN FATE: 80% f it is them excreted in feces. 20% is resrbed. Mst f that ges back t liver and is re-secreted. Sme f that ges t systemic circulatin and is then excreted in urine. JAUNDICE: Caused by bilirubin build up, indicating prblems with the liver. HEMOLYTIC JAUNDICE: Greater amunt f heme breakdwn > increased bilirubin in intestine > excessive urbilingen in feces This can be caused by Pernicius Anemia. OBSTRUCTIVE JAUNDICE: Obstructin f bile-duct, preventing Bilirubin Glucurnide frm entering intestine; it is therefre diverted t kidneys > excessive bilirubin in urine + big drp in fecal urbilingen INTESTINAL ABSORPTION: Absrptin is ultimately dependent n the Na + /K + Pump t create the gradient. SODIUM: Na + is transprted int the entercytes by three mechanisms: Electrchemical Channels: (40%) Na + simply mving with its electrchemical gradient. Na + /Nutrient Ctransprt: (30% )There are several Na + -Ctransprters, fr glucse and fr individual amin acids. Na + /Cl - Ctransprt: (30%) "Neutral" ctransprt f Na + and Cl -, bring water in with it. PERICELLULAR: Recent evidence says that majrity f fluid appears t be absrbed between cells rather than thrugh cells (transcellular), althugh bth ccur. CHLORIDE: Cl - is absrbed thrughut the intestine. POTASSIUM: Passively absrbed in small intestine, and secreted in large intestine. NEUROGENIC SECRETION: Three secretmtr neurtransmitters fr entercytes: Substance P ACh, bth preganglinic and pstganglinic VIP, Pstganglinic Inhibitry neurns act n the preganglinics t prevent secretmtr excitatin: Smatstatin Sympathetics Opiids: Patients n piids can becme quite cnstipated and get a cnditin called "Narctic Bwel." VIPOMA: Cancer causing excess release f VIP > excess secretin > secretry diarrhea. 10

11 DIARRHEA: There are tw types f Diarrhea: Secretry and Osmtic SECRETORY DIARRHEA: Diarrhea caused by hypersecretin, via t much secretmtr stimulatin r t little inhibitin. N Slute Gap -- fecal analysis is smtically nrmal r hypsmtic. The Diarrhea des nt g away after the meal is gne. ETIOLOGY: CHOLERA TOXIN: It causes increased basal levels f camp in entercytes. camp is nt nrmally active ever in entercytes. The result is that Cl - channels n luminal membrane are blcked pen > perpetual secretin. Even wrse, the txin als blcks Na + -Cl - Ctransprt, reducing absrptin f fluid. Gastric Tumr > Over secretin f Gastrin. Zllinger-Ellisn Syndrme OSMOTIC DIARRHEA: Diarrhea caused by hypersmtic blus in intestine -- it is fd-dependent. SOLUTE GAP: Fecal analysis shws a large "slute gap," i.e. hypersmtic feces. The diarrhea ges away when fd is ut f GI-Tract. LAXATIVES cause smtic diarrhea because their cntents (magnesium) are like fiber in that they are nt absrbed > higher blus tnicity. Gluten Enterpathy: Intlerance fr wheat (gluten), causing blunting f entercyte brush-brder > PROTEIN DIGESTION: decreased surface area fr absrptin > smtic diarrhea. Celiac Sprue als causes smtic diarrhea. PEPSIN: Secreted by stmach. Endpeptidase. Pepsingen > Pepsin by the actin f H + in the stmach. Mainly splits bnds between Tyr and Phe. TRYPSIN: Endpeptidase It is a Serine-Prtease, i.e. it uses Serine as its active site t cleave prteins. Trypsin is activated by ENTEROKINASE, which is secreted in the intestinal brush-brder. It cnverts Trypsingen > Trypsin CLEAVAGE-SPECIFICITY: Trypsin cuts amin acids that are adjacent t Lysine and Arginine. Aut-Catalytic: Activated trypsin acts n trypsingen t make mre f itself. Trypsin als acts n Chymtrypsingen t make Chymtrypsin! CHYMOTRYPSIN: Endpeptidase Chymtrypsingen is activated by Trypsin. CLEAVAGE-SPECIFICITY: It cleaves armatic and nn-plar side-chains. It is nt as specific in its cleavage site as Trypsin. It will cleave any f the fllwing residues: Trp, Phe, Tyr, Met, Leu ELASTASE: Endpeptidase Elastase is activated by Trypsin, t. It cnverts Prelastase > Elastase CLEAVAGE-SPECIFICITY: It cleaves residues adjacent t Alanine, Glycine, and Serine residues. CARBOXYPEPTIDASE: These are expeptidases that cleave at the carbxy-end. They are bth activated by Trypsin just like abve: Prcarbxypeptidase > Carbxypeptidase They are bth Metallprtease which require Zinc fr catalysis. This is a different mechanism than the endpeptidases which are serine prteases. These guys are secreted in the pancreas. Carbxypeptidase-A: Cleaves neutral and acidic side-chains (n the carbxy end), such as Alanine, Valine, Isleucine, Leucine. Carbxypeptidase-B: Cleaves basic residues -- Lysine, Arginine 11

12 Every time Trypsin cuts a prtein, yu are left with a prtein piece that has either Lys r Arg at the carbxy-end! Carbxypeptidase can then take ver t remve that end-piece. This in effect gives us a free amin acid f Lysine r Arginine which can then be absrbed. AMINOPEPTIDASE: Expeptidases that cut at the amin end f a peptide. This is secreted by the intestinal mucsa further alng the small intestine (jejunum). This is a metallprtease that requires Zinc and Manganese fr catalysis. This cuts, usually n smaller peptides, ne acid at a time ff the amin end. DIPEPTIDASE: An Aminpeptidase, similar t abve, which cuts tw acids at a time frm the amin end f a peptide. PROTEIN ABSORPTION: Abut 70% f prteins are taken in as dipeptides and tripeptides. They can then be further degraded by intracellular peptidases. Abut 30% are taken in as free amin acids, via Na + -Ctransprt. There are multiple Na + transprters fr the different classes (neutral, basic, acidic) f amin acids. CARBOHYDRATE DIGESTION: SALIVARY AMYLASE: Begins breakdwn f starch in muth. PANCREATIC AMYLASE: Breaks dwn alpha-1,4 (starch) linkages int disaccharide cmpnents. Secreted by pancreas int lumen f dudenum. Cellulse = beta-1,4 linkage. That is nt digestible by humans and thus cnstitutes fiber. alpha-1,6 Limit Dextrins branches can als exist in starch. They are brken dwn by ismaltase. DISACCHARIDASES: SUCRASE: Breaks dwn Sucrse > Glucse + Fructse Lcated in the intestinal brush-brder. MALTASE: Breaks dwn Maltse > Glucse + Glucse Lcated in the intestinal brush-brder. LACTASE: Breaks dwn Lactse > Glucse + Galactse Lcated in the intestinal brush-brder. LACTOSE DEFICIENCY is a very cmmn prblem. It results in smtic diarrhea. ISOMALTASE: Breaks dwn alpha-1,6 LIMIT DEXTRANS Branches in starch. Lcated in the Intestinal Brush Brder SUGAR ABSORPTION: Disaccharides gt the entercytes where they are brken dwn by disaccharidases (as abve). The mnsaccharides are then transprted as fllws: Glucse: Enters entercyte via Na + -Glucse Ctransprt, and enters bldstream via facilitated diffusin n ther side. Galactse: Uses the same Na + -Glucse transprter as abve, but it has a lwer affinity fr the transprter than glucse. S, if bth sugars are present then glucse will preferentially bind. FAT DIGESTION: Fructse: Passes thrugh membrane by simple diffusin. Glucse-Galactse Malabsrptin syndrme: Cngenital disrder; mutatin in Na + /Glucse Ctransprters. The child was successfully raised n a Fructse diet. GENERAL PROCESS f Digestin and Absrptin: EMULSIFICATION by micelles. Bile salts facilitate the attachment f Pancreatic Lipase t the lipids. There is an unstirred water layer right at the villus brder. Due t its detergent prperties, micelles can penetrate that brder. DIGESTION: LIPASE then breaks dwn the triglyceride > mnglyceride + free fatty acids. Fatty Acids diffuse thrugh entercytes by simple diffusin. RE-ESTERIFICATION: Fatty acids are re-esterified t triglycerides inside the entercytes. CHYLOMICRON FORMATION: Chylmicrns are frmed as prtein cats + chlesterl is added t the triglyceride. LYMPH: Chylmicrns enter circulatin thrugh lacteals > lymphatic system. Shrt Chain fats g directly int the prtal bld -- nt int lymph. 12

13 LINGUAL LIPASE: In the tngue. PANCREATIC LIPASE: The main triglyceride cutter. It attaches t micelles, with aid f bile salts, t facilitate Triglyceride > 2-Mnglyceride + 2 Fatty Acids PHOSPHOLIPASE A 2 : COLIPASE: Frms a "wedge" in fat glbules which facilitates attachment f lipase. OVERSUPPLY f Pancreatic Enzymes: 25% intact pancreas is sufficient fr adequate fat absrptin. There is great redundancy in the supply f pancreatic excrine enzymes. 13