physio combine

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Physiology Salivary Secretion, swallowing & esophageal motility Mokhallad Aljenabi Hamzeh Jarbou & Salah Dwiekat Monday, 24/10/2011

The Dr said that he will be discussing salivary glands, salivary secretions; esophagus which is the tube that conducts food from the mouth to the stomach, and this involves swallowing and some information about vomiting in this lecture.

The Dr started talking about salivary glands and salivary secretions (saliva) which are secreted in the mouth by these glands.

You can see from this diagram we have major salivary glands; Parotid, Sublingual, Deep and Superficial Submandibular glands.

Also we have small salivary glands called Buccal glands that only secrete mucus, and the majority of the saliva comes from the major glands.

Salivary secretions are classified according to their contents (different proportions of water and mucus).

Parotid glands produce serous secretions containing enzymes especially amylase enzyme. In the mouth, amylase is called ptyalin which acts on starch. So, when you are chewing carbohydrates, for example bread, for a long time you will start feeling sweetness in your mouth and that’s because the amylase (ptyalin) enzyme breaks starch into glucose.

Submandibular and sublingual are both mixed glands (seromucous glands).

The salivary glands release a lot of saliva during the day (1-1.5 L/day). The process is continuous even at sleeping. There is a basal level of secretion for the glands and it is increased due to certain stimulants like spicy food or if you are chewing a gum or a soft material. The secretion of saliva at the basal level (unstimulated state) comes from the submandibular gland because it is a seromucous gland and this is important to make our speaking easier.

Major flow during stimulated status especially when there is food in our mouth comes from the parotid gland. And that’s because its secretion contains a lot of alpha amylase (ptyalin).

The secretion is increased by stimulation from both sympathetic and parasympathetic nervous system but the type of the secretion is different between them.

The parasympathetic will produce vasodilatation and the water concentration in the secretion is increased (watery secretion).

In some books, they say that excitation of sympathetic decreases the salivary secretion. But, this is not 100% true because actually, it increases the salivary secretion.

This type of secretion is mucus secretion and that’s why it called viscid (thick) secretion.

Because sympathetic stimulation causes vasoconstriction, it increases the salivary secretion less than the parasympathetic stimulation. Under stressful conditions, when there is sympathetic stimulation, you feel dryness in the mouth.

Basic saliva components are: 1- Mostly water 2- Some electrolytes (Na+, K+, Ca2+, Cl–, HCO3– ) 3- Proline-rich proteins for protection of teeth enamel against caries.

4- Enzymes: A-

Ptyalin to start digestion of carbohydrates.

B-

Lingual lipase which is secreted from lingual glands on the tongue. This lipase is different from the pancreatic lipase. It is not a water-soluble protein, it is lipid-soluble. It penetrates the lipid part of the food and it is important in food digestion in some stages of our life.

5- Important substances to fight bacteria, viruses and fungi in the mouth to keep it clean and protected from them because the mouth is the dirtiest region in the body: A- Immunoglobulins mostly IgA B- Lysozyme C- Lactoferrin D- Thiocyanate ions 6- Mucin is a glycoprotein for lubrication of food and protection of oral mucosa. It makes the bolus slippery so that it can move easily in the mouth. If the bolus is not covered with mucin, it may become hard and cause injury to the oral mucosa.

The basal pH of saliva is about 7 (Less than blood) and it increases or decreases depending on the type of the food and the time of secretion. Stimulation state will increase the pH of saliva so it will be alkaline.

Now the functions of saliva: 1- Moistens oral mucosa which is important for swallowing, speaking and chewing. To facilitate chewing, it makes more water to break the food particles in smaller sizes.

In fact, the mucin layer on the oral mucosa is thought to be the most important nonimmune defense mechanism in the oral cavity.

2- Moistens dry food, lubricates food to facilitate swallowing and cools hot food.

Cooling is important in order to prevent burning the mucosa and its consequences.

3- Provides a medium for dissolved foods to stimulate the taste buds and facilitate the taste sensation. Taste buds are chemical receptors. So, we need to dissolve the material in order to be sensed and tasted.

4- Buffering the oral cavity: We have seen the pH of saliva is about 7. When we said buffering, usually we're talking about acidic material. The acidity is very bad for our teeth, so to protect the teeth we have to buffer (neutrailize) the acidity, and this is done by the saliva, especially when there's increase in salivary secretion.

So, a buffer has a high concentration of bicarbonate (HCO3-)  Towards the alkaline side.

5- Digestive function: We mentioned it. Alpha Amylase breaks the bond 1-4 glycoside bond in starch (The bond between glucose #1 & #4 in starch). We also talked about Lingual Lipase  breaking down the FAT (Triglyceride).

Alpha Amylase  Breaks the bond 1-4 glycoside in starch Lingual Lipase  Breaks down the fat (Triglycerides) 6- Sometimes, some of the gastric content is going toward the esophagus. To protect the esophagus if this thing happens, salivary secretion will neutralize the acidity, and this will help a little bit in the neutralization of the acidity.

7- It's important in mineralization of the teeth (New teeth) & also in repairing of precarious Enemal lesion. If there's a lot of saliva, this will help in protection of the teeth. Saliva contains Calcium and Phosphate (Which are important ions in formation of bone), and this helps in minimizing the tooth decay )‫(تحلل‬ 8- Lysosomes and all the other things that we mentioned are for protection against bacteria.

9- And we have also Anti-Bacterial compounds in saliva that fight against bacteria.

Lysosomes, IgA, Peroxidase  They have anti-bacterial effect.

These are some points of details about what are the functions of Lysosomes, IgA, Peroxidase & Lactoferrin:

Lysosomes: Agglutinates Bacteria. If you agglutinate bacteria, this will activate the autolysins. This activation of autolysins will lead to lysis of the bacterial cells.



IgA: interferes with the adherence of microorganisms to host tissue. (This is the first step of interaction of the bacteria and the tissue). It neutralizes viruses, bacteria, and enzyme toxins.



Peroxidase: breaks down salivary Thiocyanate. This Thicyanate once it's broken, it will act as bactericidal agent because it inhibits Glycolysis.

Saliva also contains Lactoferrin  It binds Free Iron. Binding of Lactoferrin to

iron has Bactericidal OR Bacteriostatic effect, and this will lead to less growth of Micro-organisms. This is also important in fighting against bacteria.

These are some of intra-oral complications that will happen if salivary secrection is abscent:1) Candidiasis: Infection with Candida (Fungal infection).

2) Recurrent Aphthous Ulcers: These ulcers could develop in the oral cavity, and we don't excatly what is the reason for them.

3) Dental Caries: People with less saliva or no saliva, they are subject to dental caries and all the things mentioned above.

Let's see how's salivary secretion is produced.

Salivary secretion is made and produced in the Acinus. Then it will go to small ducts (Intercalated – Intralobular – Interlobular) and then to the main duct.

The composition of Saliva is almost similar to Plasma. Saliva is composed of water + ions (Sodium, Potassium, Chloride, and Bicarbonate). When it moves through the small ducts, it will be modified. There's secretion and absorption of some ions:Potassium is secreted into the duct and in exchange Sodium will be eliminated.

Chloride will be eliminated in exchange of Bicarbonate.

For this reason, you will see that the concentration of Sodium & Chloride in saliva will be decreased. Saliva will be containing more Potassium and more Bicarbonate.

The important point here is Na+/K+ pump. This pump is under the effect of Aldosterone:If there's an increased secretion of Aldosterone  The amount of K+ will be increased and the amount of Na+ will be decreased.

Slide #9 is talking about the modifications

of

salivary

secretions.

At resting condition, flow of

saliva

is

slow.

So

the

modification in composition will be more. In this state (resting state) the concentration of ions as follows:-

Na and Cl: 15 mmol/L (If you remember, the plasma Na+ concentration is about 150 mmol/L & concentration of Cl- is 95-105 mmol/L). So it's reduced greatly.

-

K: 30 mmol/L (Normally in plasma is about 5 mmol/L)  Increased.

-

HCO3: 50 mmol/L (Normally in plasma is about 20-24 mmol/L)  Increased.

When there's basal salivary secretion, there's more time for modification of salivary secretion. If the flow of saliva is increased:

The amount of Na+ & Cl- concentration will be increased about 1/2 or 2/3 of plasma concentration.



Potassium concentration is decreased a little bit, but still more than the plasma (4 times more).



The Bicarbonate is still increased. (The doctor said that he couldn't find any reason why it's increased).



The osmolarity of the salivary secretion is increased with the increase of salivary formation, but still it's less than those the osmolarity of body fluids. That's why salivary secretion is considered as Hypotonic Secretion (Whether it's at basal level or at its maximum concentration).

Let's move to another topic which is "Mastication = Chewing", it's not very important but we should know some points about the importance of chewing.

It is important for digestion of food because:1. It breaks the cellulose membrane of the fruits and vegetables.

2. It increases the surface area on which digestive enzymes work.

3. It prevents excoriation )‫ (تجريح‬of gastrointestinal tract mucosa.

Chewing reflex: This reflex actually happens when you're not aware of your chewing. This reflux requires a stimulant, and thus there will be a response.

Presence of food bolus causes dropping of the lower jaw. When the lower jaw is dropped, this will lead to stretching of the muscles (Mastication muscles)  Will lead to activation of what's called (Stretch reflex)  This will lead to contraction of mastication muscles  Elevates lower jaw upward  This will elevate the bolus of food and it will stimulate the mouth lining (Soft & Hard Palate) to initiate another reflux  Which will keep repeating itself until the bolus of food is swallowed.

Food bolus  Drops lower jaw  Stretching of mastication muscles  Stretch Reflex  Contraction of mastication muscles  Elevates lower jaw  Elevate the bolus of food  Stimulate the mouth lining of Hard & Soft Palate  This will repeated times and times until the bolus is swallowed.

Swallowing (Deglutition) Swallowing means how we can bring the food from the mouth towards the stomach.

It is a second stage of food ingestion (The first one was mastication). As far as swallowing is concerned, we have three stages:1) Voluntary  You start it & and you can stop it at one time or another.

2) Pharyngeal  Involuntary.

3) Esophageal  Involuntary.

(If you reach the involuntary stage  It will continue until the food reaches the stomach (You can't stop it) ).

Let's discuss them by details:1) Voluntary stage: It's in the mouth. By your will, the bolus will be pushed backward to start the swallowing. When you finish chewing, it becomes like one piece (bolus)  The person will push the bolus by the tongue upward Tonsillar Pillar

against the palate & this will initiate a reflux (Reflux  Involuntary stage). So this stage will end when this bolus is pushing the Tonsillar Pillar  This will initiate the reflux because they're some receptors in this area that will be stimulated, and once they're stimulated, impulses will be sent to swallowing center, and once it's stimulated  The involuntary stages will start.

2) Pharyngeal stage: Involuntary stage. It starts by stimulation of the receptors in the Tonsillar Pillar & in the early parts of the pharynx. Once the swallowing center is stimulated, impulses will be sent from the swallowing center towards different parts in order to continue the swallowing act.

*) Some important points about the pharyngeal stage:-

Bolus entering Esophagus and UES relax

A) Pushing the soft palate upward to prevent the reflux of food into the nasal cavity.

Pushing the soft palate upward will obstruct the posterior opening of the nasal cavity  Prevents the movement of food towards the nasal cavity.

(From anatomy: By muscles of Levator Velli Palatini & Tensor Velli Palatini).

B) Prevent the food from passing into the trachea. And this is done by:1. Approximation of Vocal Cords medially.

2. The larynx is pulled upward.

3. Epiglottis swings back over the opening of larynx.

C) Palatopharyngeal folds are pulled medially. This is important to make sure that only the good chewed food can be passed. If it's a big bolus (Not well masticated), it will be difficult to pass into this opening (Between the Palatopharyngeal folds).

D) Relaxation of upper esophageal sphincter to allow the food to go to the esophagus.

E) Pharyngeal muscle contraction starts (peristalsis) from upper parts and spreading downward. Once the Peristalsis occurs in the Pharyngeal muscles, it will continue to the esophagus.

And actually the esophagus peristalsis is considered as continuation of Pharyngeal peristalsis.

We also have to stop respiratory activity during swallowing. So, once the swallowing center is stimulated by impulses coming from the mouth, inhibitory impulses will go from the respiratory center to the respiratory muscles to stop breathing (This is important as the DR said) ďƒ This will prevent any possibility of the food bolus to go towards the larynx (Trachea).

For the pharyngeal stage, it's a very short stage that lasts for less than 2 seconds.

The upper esophageal sphincter (the upper 3 cm of esophagus) is closed all the time except during swallowing (Will be relaxed at the end of the pharyngeal stage ďƒ In other words, at the beginning of Esophageal stage).

The sensory information initiating swallowing reflex is carried by 5th (Trigeminal) and 9th (Glossopharyngeal) cranial nerves.

The motor orders from swallowing center to pharynx and esophagus are through 5th,9th,10th,12th cranial verves and few upper cervical spinal nerves.

3) Esophageal stage: Continuation of Pharyngeal stage.

Peristalsis means the contraction of one part of GIT and relaxation in the other part. This facilitates the movement of the food through the tube (Esophagus).

It's a continuation of the Pharyngeal peristalsis because smooth muscles of Pharynx and Esophagus are in continuation with each other.

It takes about 10 seconds for this peristalsis to push the bolus from the beginning of the esophagus till it reaches the stomach.

We have two types of peristalsis here:A) Primary Peristalsis: For this peristalsis to occur, you need Vagal pulses. That's why bilateral cervical vagotomy will abolish this peristalsis. (In other words, if the vagus is cut or not functioning well, this peristalsis will not occur).

B) Secondary Peristalsis: Doesn't occur normally all the time (Not part of normal swallowing reflex). This peristalsis occurs when primary peristalsis fails to push the bolus towards the stomach (Large bolus, constriction … etc). Very important point to remember that this peristalsis DOESN'T DEPEND ON THE VAGUS  Instead it depends on spontaneous contractility of the smooth muscle in the esophagus.

If the food is stuck, this will lead to stretch of esophageal wall. This stretch of esophageal wall will stretch the muscle, and once the muscle is stretched  This will initiate contraction.

Secondary Peristalsis is due to stimulation of the myentric plexus in the wall of esophagus and it will continue after vagotomy.

We have to overcome the resistance of bolus being pushed from esophagus towards the stomach. So for this reason we have a Sphincter. Some anatomists consider it as Functional Sphincter.

It's between the lower part of esophagus and the stomach. This sphincter prevents materials from passing from stomach towards the esophagus (Like in coughing, increase in Intra-Abdominal pressure, pushing the stomach contents … etc.)

Note: LOS means Lower Esophageal Sphincter If this sphincter isn't functioning well, there's a chance of some stomach content to pass backward towards esophagus. So it's very important sphincter.

Some important information you have to know about this sphincter:1) This sphincter has pressure. At rest, it's about 30 mmHg. 2) Failure of LOS relaxation causes Achalasia (Movement of food or fluid from esophagus towards the stomach very difficult).

3) Failure of LOS contraction causes reflux of stomach content to esophagus causing Reflux Esophagitis.

Why we need this LOS? Because some actions cause elevation in the Intra-abdominal pressure, the sphincter will close to prevent the backward flow of stomach contents towards the esophagus.

This sphincter can be closed either by:1) It's muscle.

2) Functional Position ďƒ It acts like valve.

The movement of food bolus from esophagus to stomach needs Receptive relaxation. Receptive relaxation simply means if you want to push the food bolus from location #1 to location #2:Location #1 muscles should be contracted to push the food bolus WHILE muscles of location #2 should be relaxed in order to receive the food bolus. And this process shall be repeated many times in order to food bolus to reach the stomach.

Done By: Hamzeh Jarbou & Salah Dwiekat

Physiology, lecture (2)

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Physiology Vomiting and Gastric Secretions Mokhallad Janabi Asma' Abu-Salah Tuesday, 25/10/2011

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Physiology, lecture (2) Physiology, lecture (2) Dr. Mukhallad Al janabi Done by: Asma Abu-salah

Vomiting and Gastric secretions

Vomiting: The sudden and forceful expulsion of gastric and upper intestinal contents and it is a reflex (when reflex is mentioned it means: there is a stimulus and there is a response) The stimulus comes from: a) Mostly , the stimulation is from the upper gastrointestinal tract like bad food, irritation , distention or what ever b) Or it can be from some stimuli specially when there is excitation of the chemoreceptor center such as seeing bad image or from a bad smell but

How does this reflex walk??

Mainly 3 ways: 1.

2.

Impulses will be carried by vagus nerve  going to a certain place in the medulla oblongata which is called vomiting center  cretin events or orders to accomplish the vomiting action.

Some of the impulses may come from the CHEMORECEPTOR TRIGGER ZONE which is found on the floor of fourth ventricle of the brain where any substance in the blood , toxic material in the blood (or any emetic substance )will produce an effect  which will be transmitted directly to the CHEMORECEPTOR TRIGGER ZONE  impulses go to the vomiting center  once it is stimulated, the action of vomiting will start -- till it is completed , so that is how we can evacuate the material from stomach and upper GIT ✎ It is also stimulated by impulses coming from vestibular apparatus. motion sickness is due to stimulation of vestibular apparatus which will lead to the activation of the vomiting center ✎ it is unknown whether the vestibular apparatus activates the chemoreceptor zone first or directly activates the vomiting center

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Physiology, lecture (2)

✎ BUT in order to induce vomiting reflex , you have to stimulate the vomiting center because all the impulses to the respiratory center , to the abdominal muscles, to increase intragastric pressure are sent from this center

Emesis action: Vomiting action is triggered by one or more of the following stimuli which will affect vomiting center: a. b. c. d. e. f. g.

excessive gastric or duodenal distension noxious substances in stomach certain smells or sights emotional factors touch receptors at back of throat reflexes involving semi-circular canals (‘motion sickness’) stimulation of the ‘chemoreceptor trigger zone’ by circulating ‘emetics’

?? Which of the factors is responsible for morning sickness in pregnancy?

It is mostly CHEMORECEPTOR TRIGGER ZONE because during pregnancy it seems that some toxic materials develop in the body, or some hormonal effect may induce this trigger zone.

Sequence of events in order to finish vomiting: • Deep inspiration, respiration held in mid inspiration • Closure of glottis • Relaxation of lower esophageal sphincter ,, in order to allow the substance to pass from the stomach to esophagus ✎ We need something to increase intra abdominal pressure to press on the stomach in the upper GIT in order to make this expulsion of materials which is done by Contraction of diaphragm and abdominal muscles. This contraction causes increase in the intra-abdominal pressure(since the contraction of the diaphragm descending of the diaphragm)+ contraction of the abdominal muscles  increase in the intra abdominal pressure Page 3

Physiology, lecture (2)

• Duodenal contraction (reverse peristalsis), so instead of the materials going to the anal side, it will go in the reverse side toward the esophagus and since the lower esophageal sphincter is open , the materials will be allowed to go outside ✎ glottis must be closed in order to prevent aspiration of materials toward the lung

The autonomic effects associated with vomiting : - sweating - tachycardia - Salivation ✎ If you lose only gastric contents metabolic alkalosis (because of the loss of the acid from the stomach ) ✎ If you lose large amount of both gastric and duodenum  metabolic acidosis (first of all you lose the gastric contents then you lose the duodenal contents which are basic in nature because it contains bicarbonate ,, so that will lead to metabolic acidosis

Gastric secretions: There are different types of cells that produce different substances (used for many different functions such as the substances used for absorption of vitamin B12 or for digestion and so on)

Types of Gastric gland: 1. The oxyntic glands (80% of gastric glands)-found in the body and fundus 2. Pyloric glands (20% of gastric glands)- antrum region ✎ These glands have different types of cells ,, each one performs certain function

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Physiology, lecture (2)

✎ There are 2 types of cells secreting mucus which is very important in the stomach for protection purpose (since we are taking about space filled with acid and pepsin so we have to protect the epithelium very well)

Types gastric cells : 1. mucous neck cells (secrete mucus) 2. surface epithelial cells (secrete mucus) 3. chief cells (secrete pepsinogen which is an inactive proteolytic enzyme ,, to be activated it must be converted to pepsin later on ) 4. G cells: hormonal secreting cells (secrete gastrin - in antrum) 5. parietal (oxyntic) cells (secrete HCl and intrinsic factor)

?? What is the difference between the 2typs of glands??

Both of them have chief cells and parietal cells "but mostly the parietal cells are present in the fundus and the body and little in the pylorus",, so the main difference between the 2 types of cells is only the location

Slide 2 : this is just a diagram that shows different types of cells It shows the structure of a gastric exocrine secretory gland We can see . mucous neck cells , chief cells, parietal cells ✎ sometime they call the parietal cells as oxyntic "which secrets HCL and intrinsic factor " and chief cells as peptic "which secrets pepsin "

Gastric secretion: The amount : 2L of gastric juice per day

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Physiology, lecture (2)

secretion is isotonic, pH 2-3 (in stomach lumen) "actually when gastric juice is secreted from the parietal cells the pH is less than this value ,,but because of the presence of food and mucus in the lumen of the stomach which are responsible for the increasing the pH to 2-3 "

Functions of gastric secretion: 1. Intrinsic Factor: - (from parietal cells), very important for vitamin B12 absorption in lower small intestine (terminal ileum). ✎ B12 is needed for formation of RBCs ,, so deficiency of vitamin B12 will lead to pernicious anemia" which can be due to:  either deficiency in vitamin B12 intake  or it is taken normally but it is not absorbed due to the absence of Intrinsic Factor such as if the parietal cells are destroyed due the autoimmune disease "gastritis " or gastrostomy B12 deficiency  pernicious anemia "  Both vitamin B12 and intrinsic factors are absorbed from the terminal ileum,, so if this site is missed  pernicious anemia ✎ The Intrinsic Factor is indispensable substance in gastric juice.

2. Mucus: protects gastric epithelium. It adheres to gastric surface and prevents H+ and pepsin eroding the mucosa; failure of this process leads to gastric ulceration. ✎ This type of gastric mucus has very peculiar properties which is the strong adhesion to the gastric mucosa and is not easily soluble in water in comparison to the ordinary mucus which is highly soluble in water ,,so it can be removed very quickly.

3. HCl - from parietal (oxyntic) cell: Function of Gastric acid  to kill micro-organisms but H. pylori ( which is resistant to HCL ) survives by making ammonia from urea using urease enzyme(to form an alkaline media ).

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Physiology, lecture (2)

 to activate pepsinogen (cleaved to form active pepsin which in turn initiates protein digestion )  breaks down connective tissue in food  denatures protein

4. Pepsinogen  produced from chief (peptic) cells  conversion of Pepsinogen to pepsin (active enzyme) requires low pH; optimum pH for its activation is( 1-2) which is provided by HCL

Mucosal Protection of gastric epithelium 

Since we are dealing with HCL and pepsin, it is very important to have this efficient strong powerful protective mechanism)mucus layer) :



–

a gel about 1 mm thick

–

secreted by neck cells and surface epithelium

–

can be cleaved by pepsin so continual production is required, (the Dr. commented :this is not 100% true , because although it is cleaved but it’s still strong ).

–

mucus release is stimulated by acetylcholine from nerve endings (parasympathetic )

–

it is rich in bicarbonate "important for acidity neutralization " 

HCO3- content creates a "micro-environment" around surface cells to prevent acid damage(HCO3- is needed very close to the epithelium )



HCO3- secretion is inhibited by adrenergic input (prominent in stress!) "important in hypothetical point of view which may explain why stressful condition may lead to peptic ulcer which is due to decrease in bicarbonate "

prostaglandins are protective agent o increase mucus production which is rich in bicarbonates o increase blood flow to the gastric epithelium

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Physiology, lecture (2)

✎ so ,, inhibition of prostaglandin production less protection to the stomach and this is what happen when you are receiving NSAIDs so it will inhibit cyclooxygenase  ↓in PG formation  less HCO3 ↑ liability of the stomach epithelium to develop ulcer  inhibition of enzymes involved in prostaglandin production (cyclooxygenases =COX) by NSAIDs (non-steroidal anti-inflammatory drugs) such as aspirin, ibuprofen, etc.=>> results in gastric damage .

slide 6 : This is the epithelium , and the mucus layer (1mm thick )and it forms a barrier between the contents and the epithelium

2 types of mucus are present: 1. The surface epithelial cells of the stomach secrete thick insoluble, unstirred mucus (which means it is not easily removed because it is insoluble in water  sticky to epithelium) that lines the surface of the stomach.  This mucus contains glycoproteins that form an almost gelatinous coating which contains relatively high concentrations of bicarbonate ion.  This coating protects the stomach epithelium from gastric acid and pepsin. ✎ Glycosylation of mucin makes it relatively resistant to proteolysis by pepsin ✎ If the mucus is removed  this will lead to exfoliation of the stomach 2. A second type of mucus (soluble mucus ) is secreted along with the gastric juice from deep cells of the gastric pits o it is protective for the epithelium of the gastric pits and it pushes the material toward the lumen

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Physiology, lecture (2)

o to coat and lubricate the food bolus and facilitate mixing. o Soluble mucus restricts the access of gastric juice to the gastric pit epithelial cells.

Slide 8:  

Parietal cells secret HCl and intrinsic factor,, the mucus push the materials and the contents toward the lumen of stomach

HCl secretion: Factors increasing HCl production from parietal cells: 1. Acetylecholine: released from cholinergic nerve fibres of the (parasympathetic nerve ending ) acts on muscarinic receptors (their type is M3 ) 2. Gastrin: released from G cells of pyloric glands acts on G receptors, under cretin stimuli  Gastrin will be secreted from G cells to the blood  will go to the parietal cells acting on their receptors 3. Histamine: released from :(1)enterochromaffin-like-cells (ECL) in the stomach and (2)mast cells acts on H2 receptors. ✎ H2 receptors. inhibited by H2 receptor antagonists (eg. cimetidine) ✎ ECL & cells secreting Histamine are stimulated by gastrin and acetylcholine ✎ each one of the three stimulants potentiates the effects of the others. e.g. stimuli stimulating vagus nerve release of Ach  acting on muscarinic receptor + going to the cells producing histamine  histamine releaseHCl production (so it seems that there is a sort of potentiation between different factors )

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Physiology, lecture (2)

The mechanism by which HCl secretion is increased by the effect of the previous factors: ✎ HCl is simply H + and Cl – ✎ The following factors actually function to  increase H +/K+ ATPase carrier to increase the production of H +  more Cl- channels inserted  So We can get more HCl because of more H+ & more Cl-

Paracrine hormones and HCl release in the gastric phase of secretion: (slide 10) ✎ PARACRINE HORMONES : are HORMONES produced by a cell and affecting Neighbor cells (not to the blood )"local hormones " In contrast to the endocrine : which are ordinary hormones released by cells to the blood and distributed every where a) Histamine: Released from mast cells in mucosa by Ach (from nerves) and gastrin ( from G-cells)  Acts directly on parietal cells(through H2 receptors) to stimulate HCl production.  H2-receptor antagonists block action or the release of histamine b) Somatostatin: Released from D-cells in gastric epithelium by direct action of H+ (at lumen pH < 2).  Reduces gastrin release → reduced HCl secretion i.e. if HCl release is increased  Somatostatin will be secreted in large quantities and this is a way of protection because Somatostatin  inhibit gastrin secretion( from G cells)  less HCl secretion protection ,,  if this protection is not there  peptic ulcer may develop slide 11 :

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Physiology, lecture (2)

this figure looks complicated but you will find it easy if you follow it

 G cells are found In the antrum, (1)presence of certain food OR (2) decrease in the stomach acidity  activation of G cells  gastrin production  Gastrin secreted into the circulation  HCl production due to  stimulation of either i. Directly G receptors to the parietal cells or ii. Indirectly cells which produce histamine  Also we can see the vagus nerve ,, its end is producing Ach  acting on muscarinic receptor(M3)  increase HCl So >>all of these factors (gastrin, histamine and stimulation of muscarinic receptor ) => increase the production of HCl "and there is some potentiation"

?? Do the G cells have autocrine activity ?

No, the stimulus for the G cells should be either food (specially amino acids ) or decrease in the HCl and so increase in the pH And about gastrin ,, it is a real hormone(endocrine hormone ) ,, secreted by G cells  go through the blood although it is sometimes called as a local hormone because it is acting on certain part of the body

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Physiology, lecture (2)

Mechanism of HCl formation: H ions & Cl – are needed for the HCl to be formed For H  we need active transport For Cl  different hypothesis either active or passive secretion

First hypothesis:  For H+  simply coming from CO2 by the influence of carbonic anhydrase enzyme CO2 + H2O --- carbonic anhydrase ----- H+ + HCO3 –  H+ will be pushed against very high concentration gradient more than 1000000 times(from inside the cell where the pH = 7 to the lumen where the pH = 1)so we need very active transport which is achieved by K+/H+ ATPase carrier which will push the H+ to the lumen of the stomach and taking the K+ to the interior of the cell  For Cl -  moves out (by diffusion) from parietal cell into lumen through electrical gradients from high con. To low con.  In order to make high concentration of Cl - inside the parietal cell we need to push the Cl - to the interior of the cell , and this is done by counter transport of Cl - with HCO3 (between the blood and the parietal cell at the basal side )

 HCO3 is formed in the interior of the cell so it will produce high con.  to the blood side where there is a low con. Of HCO3 -- this gradient will be used by the Cl -  so it will move into the cell against con. Gradient  The end result is more HCl in the lumen ✎ ** the HCl secretion can be reduced by inhibition of H+/K+-ATPase (i.e. proton pump), "we talked about proton pump inhibitor " or by blocking carbonic anhydrase enzyme

Page 12

Physiology, lecture (2)

Second hypothesis: The principle is almost the same    

carbonic anhydrase is needed in the formation H+ from CO2 + H2O H+ is pumped against very high con. Gradient by H+/K+-ATPase The end result of this transporter is pushing H+ against con. Gradient For Cl- : there is diffusion at the basolateral aspect (from extracellular to intracellular )  Active transport of Cl- to the lumen of the stomach  So here both H+ and Cl- are both actively transported In both of the scenarios the HCO3 will move to the extracellular fluid either by diffusion or by counter transport and for this reason the HCO3 in the blood leaving the gastric area will be more and this is called alkaline tide

The Dr. Is reading from the slide…

• * The K+/H+ pump is very powerful and requires appreciable amount of energy because H+ is pumped against more 1000000 concentration gradient (pH 7 to pH 1) ) ✎ **the 1000000 because we are dealing with the pH which is the logarithm of the real con.

- It can concentrate H+ 3 million times.

Page 13

Physiology, lecture (2)

- Inhibition of this pump by drugs called proton pump inhibitor (Omeprazole) helps in reducing the amount of HCl secretion.

• The pH of parietal cell secretion into canaliculi is very low (may reach to about 0.8). "so the difference in the gradient is still more than 1000000" Slide 15: This is just to give you an idea about pH before the meal and after the meal

Before the meal  basal After eating  the HCl will be diluted  ↑in PHbecause of the continuation of secretion  the PH will be reduced again

For inhibition of gastric acid secretion: Stomach – somatostatin Duodenum – secretin, hyperosmotic chyme fatty acids

I'd like to thank all my sweet friends specially those who helped me in the correction of this lecture;) sweet friends,, I will miss u all Best wishes for all ✿✿

The End Done by: Asma

ヅ

Abu- Salah ◕‿◕

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23 / 59 3/7 25

Physiology Gastrointestinal and Pancreatic Secretions Mokhallad Janabi Haya Mesmar Tuesday, 1/11/2011

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Tuesday, 1/11/2011 Physiology lecture 3 Done by: Haya Mesmar.

Gastrointestinal & Pancreatic Secretions Today we will continue talking about gastric secretion and some points about secretion from other sites in the GIT, and then we will describe pancreatic secretion, the composition of pancreatic secretion and so on…

Gastric secretion means secretion from the stomach, these mostly are: hydrochloric acid plus pepsinogen…

When we say phases, we mean the gastric secretion is happening in stages, these are: 1- Cephalic phase: impulses from the head. Contributes only for 30% of the whole gastric secretion.

2- Gastric phase: from stomach. Triggered by presence of food in the stomach. The major contributory phase in the gastric secretion (more than 60%).

3- Intestinal phase: from the intestine. The least contributory phase in the stimulating effect of gastric secretion. >> Cephalic phase: from the diagram in slide 17: In summary, taste, smell or even thinking of food and the tactile sensations in the mouth, all of these will work as stimuli and send impulses to the medulla oblongata, and from there these signals go through the vagal nerve.

If you remember, when we stimulate the parietal cells, for example, by AcytileCholine through the parasympathetic fibers, it will increase the secretion… so it’s mostly a parasympathetic stimulation…

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Gastrin is secreted when the pH is high and will stimulate the parietal cells to produce H+... so the parasympathetic fiber stimulates the gastrin hormone which will lead to more hydrochloric secretion.

>>Gastric phase: look at the diagram in slide 18: 1- Impulses coming from the stomach due to distention or presence of food will go to the medulla oblongata through the Vagus nerve (sometimes itâ&#x20AC;&#x2122;s called the Vagovagul reflux) and stimulate the parasympathetic fiber. And that will increase gastric secretion from the stomach.

2- Other local reflexes caused by distention of the stomach may lead to secretion of histamine or stimulation of neurons in the stomach, and this will lead to more stimulation for the secretion.

>>Intestinal phase: it means secretion from the stomach due to a stimulatory effect from the intestine. They found that it is largely hormonal, meaning that some hormones secreted from the intestine (duodenum) will go to the stomach to increase or decrease the gastric secretion. The initial stimulatory effect is through the Gastrin hormone coming from the intestine. The feedback inhibitory effect is through the Secretin hormone (coming from the duodenum) and the Gastric Inhibitory polypeptides.

From the diagram in slide 20: the presence of food in the duodenum will either stimulate the inhibitory effect by secretion of secretin or gastric inhibitory polypeptides, or it will stimulate the stimulatory effect by the secretion of Gastrin.

Secretion from the other organs: >> Esophageal secretion: The esophageal secretion is mostly protective and mucous in nature. Normally, food stays in the esophagus for a very short time. But if the opposite happened, Page | 3

this mucous secretion is important to reduce the effect of food on the epithelium of the esophagus, meaning preventing mucosal excoriation.

There’s a small possibility that the gastric content would return back to the esophagus if the lower esophageal sphincter is not competent, and because of this mucous secretion there’s some protection against this refluxed gastric juice, but we cannot rely on it completely. An increase in the intra abdominal pressure might lead to reflux of the gastric fluid towards the esophagus even in people who have patent sphincters. But we cannot rely on the mucous secretion because constant exposure to this effect will end in Esophagitis and other abnormalities. >> Duodenal secretion: It is protective since it contains a lot of mucous and bicarbonate ions. Gastric secretion going to the duodenum is very acidic so if there’s no protection against this high acidity we will end up with ulceration and irritation of the mucosa.

This mucous secretion comes from special glands called Brunner’s glands which are found in large numbers on the duodenal wall in a place where it’s highly needed ; between the pylorus where the gastric content comes from , and the Ampulla of Vater where pancreatic and billiary secretions come from . Pancreatic secretion and the bile are alkaline secretions.

So we have to protect the early part of the duodenum by the Brunner’s gland, Brunner’s gland secretion is stimulated by: 1. Tactile or irritating stimuli on duodenal mucosa: one of these that can cross your mind is the presence of food or hydrochloric acid.

2. Vagal stimulation: will increase the bicarbonate secretion 3-Secritine hormone is produced when the acidity is high, so it will trigger these Brunner’s gland to secret the mucous which will protect the duodenum.

This secretion is reduced (inhibited) through the sympathetic stimulation.

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When these Brunnerâ&#x20AC;&#x2122;s glands are not functioning well or not secreting enough mucous or bicarbonate ions, it will lead to irritation of the duodenum through the gastric secretions. >> Secretions From the small intestine: It gives about 2 liters per day: 1.8 of secretions per day.

We have 2 types of secretions: 1- Secretion from goblet cell, they secret mucous which is protective. Food is converted to chyme and doesnâ&#x20AC;&#x2122;t affect the epithelium but because of the segmentation and peristalsis happening in the intestine; there will be protection against irritation and mechanical pressure.

Mucous secretion is also important for lubrication of food and binding with some bacteria and Immunoglobulins.

2- Secretion coming from the Entrocytes, the real intestinal cells. They secrete alkaline watery fluids; we need alkaline in the intestine for the proper functioning of the digestive enzymes.

And this fluid contains sodium, bicarbonate and chloride which are needed for the absorption.

--- Mechanism of secretion: Bicarbonate and chloride are being actively secreted, and because these ions are secreted towards the lumen, water is being secreted with them towards the lumen by osmosis. ď&#x201A;ˇ We have other cells called Paneth cells, some people would describe them as endocrine cells, and they found that these cells produce antimicrobial agents so they are considered as protective cells.

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>>Secretion of large intestine: The large intestine secretes mucous and a lot of bicarbonate ions for protection.

With the possibility of formation of acid in the large intestine due to the process of fermentation and the activity of bacteria, we need the bicarbonate.

Bicarbonate is secreted through the epithelial cells by non-mucous secreting cells, so we have two types of secreting cells: 1- mucous glands secreting mucous and 2- non mucous cells secreting bicarbonate.

The factors affecting the secretion in the large intestine: - Tactile stimulation of epithelium lining the intestine.

- Local nervous reflexes: Enteric nervous fibers.

- Stimulation of parasympathetic nerve fibers.

These factors increase the secretion in the large intestine.

Functions of Mucus a. Protection b. Neutralization of acids formed in the large intestine

Pancreatic secretion: The pancreas consists of 2 parts: 1- Endocrine part: secretes the famous hormones: Insulin, Glucagone and others.

2. Non endocrine part: This aids in the digestive functions, having exocrine glands that secrete powerful digestive enzymes.

The diagram in the paper slide #1 shows the structure of pancreas: The pancreatic gland is divided into 2 parts; the acini cells and the duct (through which the secretions move from the acini to the duodenum).

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We can see that we have to types of cells: acinar cells in the acini, and cells lining the duct each of which secrets different materials.

ACINAR CELLS: these cells contain vesicles that are called the Zymogen granules.

These granules contain the digestive enzymes that are being secreted from these cells.

CELLS LINING THE DUCT: these cells secret watery secretions plus bicarbonate which is important in neutralizing the acidity and to provide optimal condition for the intestinal digestive enzymes to work, they optimum activity requires a PH of 7 to 7+.

Different small ducts are united to form the major pancreatic duct: pancreatic duct of Wirsung  Some people have another small pancreatic duct, an accessory duct, called the duct of Santorini.

The major pancreatic duct and the common bile duct unite to discharge their secretions into the duodenum.  There’s the sphincter of Oddi which is a smooth muscle controlling the opening of the major pancreatic duct.

Types of pancreatic secretion: 1- Enzyme rich fluid from the acinar cells within the zymogen granules 2- Watery secretions those are rich in bicarbonate from the epithelial cells lining the duct.  The amount of secretions is estimated by 1 – 1.5 L of pancreatic juice per day.

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Most of the digestion actually happens by the pancreatic digestive enzymes, the pancreas has all types of digestive enzymes in the pancreas.

We can divide them according to their functions into: >>Proteolytic enzymes: acting on protein. >>Amylase: acting on carbohydrates. >>Enzymes acting on fat. >>> Proteolytic Enzymes: 12345-

Trypsinogen Chemotrypsinogen Procarboxypolypeptidase Pro – elastase: acting on elastin.

Ribonuclease and deoxyribonuclease : acting on DNA and RNA proteins in The cell…

Each one of the previously mentioned enzymes acts on certain part of the polypeptide chain.

These enzymes act on proteins, that’s why they have to be secreted in an inactive form, if they were to be secreted in an active in the pancreas this will lead to the l digestion of the pancreas and its duct! So they are secreted in an inactive form in the pancreas and activated upon their entry into the duodenum when they’re needed. >>>Pancreatic amylase:  It is similar to salivary amylase.  It acts on starch and glycogen but not cellulose which is not digestible in humans.  It’s secreted in an active form and doesn’t need to be activated.

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>>>Pancreatic enzymes acting on fat 1- The Major one is pancreatic lipase : It acts on neutral fats and converts them to fatty acids and monoglycerides which are the final forms of fat for absorption, they are absorbed easily. It’s secreted in an active form.

2- Cholesterol esterase : From the name you can tell that it causes hydrolysis of the cholesterol esters (form of fat).

3- Phospholipase : It splits fatty acids from the phospholipids It’s secreted in an inactive form and is activated trypsin as explained later on.

4- Colipase : It helps in the digestion of fat by helping pancreatic lipase into making it more efficient for attacking the fatty material.

Its inactive form is called “Procolipase”, when it’s activated in the intestine lumen it will form the Colipase which will aid pancreatic lipase in its function.

Regulation of pancreatic secretion: We have 2 types of regulators : A) HORMONAL: hormones secreted from certain parts acting on the pancreas whether on the acinar cell or the duct itself .

B) NEURAL : parasympathetic and sympathetic .

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>>> Hormonal regulators: We have 2 important local hormones : 1- Cholycystokinin (CCK ) :  It acts on the gall bladder, and it’s related to a condition called cholycystits . Previously it used to be called cholycystokinen-pancreozinin ; acting on the gall bladder and the enzymatic secretion of the pancreas.  It’s secreted from (I cells of the duodenum ) , it is the primary stimulant of enzymatic secretions from the pancreas .  CCK ‘s effect is to from pancreatic secretion rich in Enzymes .  CCK is triggered by the digestive products mostly fat and proteins .

2-secritin:  a hormone of a MW of 3400  produced by S cells (S for Secretin) of the duodenum and jejunum  It causes secretion of pancreatic fluid rich in bicarbonate and water , it’s useful in neutralizing the acidity , and we will see that the major stimulus of Secretin is Hydrogen ion.

When Secretin is used to stimulate the pancreatic gland, you will end up with watery secretion unlike the hormone CCK which will end it up with enzymatic secretions.

>>Note: The secretion of Secretin hormone is triggered by stimulation of chemoreceptors by a chemical substance ; Hydrogen ions . So if there’s an acidic chyme coming to the duodenum it will lead to stimulation of the S cells and its chemoreceptors and the production secretin .

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>>>Neural regulators: We have the parasympathetic stimulation which will increase the secretion of the Enzyme rich fluid by the release of Acetylcholine While the sympathetic has mostly inhibitory effect, decreasing the pancreatic secretions, how is that? By causing vasoconstriction that will lead to less fluid secretion.

The diagram on paper slide #4 explains everything about the duodenal secretions: >>When the chyme is coming from the stomach to the duodenum, it consists of acid and partially digested food ( fat , proteins ..) . You can see that the major stimulus for CCK production by I cells is the presence of proteins (peptides) and fat, and partially the presence of H+.

For Secretin the major stimulus is the presence of H+. Fat can also stimulate the S cells leading to production of Secretin but in a very small way. >>CCK goes to the acinar cells to stimulate enzymatic secretion, while Secretin hormone stimulates the duct cells to produce the watery secretion. ď&#x201A;ˇ Notes:** partially digested proteins cause secretion rich in Enzymes ** Fats cause secretion of fluid containing Enzymes, water and Bicarbonate. **HCL causes secretion of Watery fluid and little enzyme

Activation of pancreatic Proteolytic Enzymes: Activation of proteolytic enzyme occurs by the use of another enzyme , Enterokinase enzyme, this enzyme comes from the epithelial cells of the intestine, we call them the brush border cells of the intestine, this activation happens as follows : Page | 11

Enterokinase acts on trypsinogen converting it to trypsin Trypsin acts on trypsinogen (to produce more of the trypsin) and other precursors of this digestive enzyme like chemotrypsinogen and procarboxypolypeptied converting them into more active enzymes: chemotrypsin and carboxypolypeptide.

All these active forms will act on different parts and bones of the polypeptide chain.

Trypsin will also activate some of the enzymes acting on fat which are the phospholipase and colipase .

So if the Enterokinase is absent there will be less digestion of proteins primarily, and part of fat digestion. *** This activation must happen in the lumen of the intestine (in the duodenum), and not in the pancreas.

We have many important mechanisms to prevent proteolytic activation in the pancreas, if this activation happens inside the pancreas secreting trypsin inhibitor by aciner cells of the pancreas will take place, sometimes this trypsin inhibitor is not present sufficiently and that will lead to the occurrence of pancreatitis. ď&#x201A;ˇ But in what conditions will there be activation of the Proteolytic enzymes off place?

If the pancreatic duct is blocked by viscous pancreatic juice, trypsinogine can be activated into trypsin, and as we said before this trypsin will end up in activation of all the enzymatic precursors, if there is not enough trypsin inhibitor to inhibit trypsin the end result would be acute pancreatitis: digestion of the pancreatic tissue leading to its inflammation. >>> Bicarbonate secretion from the pancreas: ď&#x201A;ˇ Bicarbonate secretion provides protection by providing an alkaline media in the duodenum for the proper functioning of the digestive enzymes we Page | 12

already mentioned. It is needed to neutralize the acidic chyme coming from the stomach Bicarbonate is under the control of Secretin: H+ stimulation of chemoreceptors  Secretin secretion going through the blood to the pancreas  releasing more bicarbonate (HCO3) >>Mechanism of bicarbonate secretion: We have carbonic anhydrase in the pancreatic duct cell, under the effect of this carbonic anhydrase water and CO2 combine to form carbonic acid which will be dissociated to form H+ and bicarbonate.

--Bicarbonate will be actively transported into the lumen.

--hydrogen will be pushed outside toward the blood and the intestinal fluid.

--sodium is transported by diffusion from the blood through the ductal cells to the lumen; the end result would be sodium bicarbonate in the lumen. >>Brunner’s glands: PH of the Brunner’s gland secretion is alkaline 8-8.9, we need to neutralize the acid, so we will end with PH around 7-7.8 and this is good for the proper function of the digestive enzyme.

They are mostly found at the early part of the duodenum.

We already mentioned the stimuli of these glands which are: 1- tactile or irritating stimuli ( hydrogen ions) 2- vagal stimulation 3- secretin hormone And the stimulus that decreases the secretion is the Sympathetic secretion.

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>>> Phases of pancreatic secretion: They are not very important but here’s a quick review: 1- Cephalic secretion: they found that there’s a little secretion coming from the pancreas before food reaches the mouth: so smell, sight, taste or even the thought of food can stimulate pancreatic secretion.

This phase plays a very little role in the secretion 2- Gastric phase: very little contribution, about 5 to 10 % of the total enzymatic secretion. Food inside the stomach will cause vagal stimulation and trigger more pancreatic secretion.

3- Intestinal phase: it has the largest share of stimulatory effect on the pancreatic secretion, about 80 – 90 %.

We have two major stimuli as we already mentioned: 1- through the H+  Secretin secretion  pancreatic secretion rich in Bicarbonate, sodium and low concentration of Chloride ions 2 - Digested protein and fat  secretion of CCK secretion of fluid rich in enzymes.

Done by: Haya Mesmar Good luck 

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29/59 4/7 25

Physiology Biliary Secretion Mokhallad Janabi Khalid Al-Qudsi Thursday, 3/11/2011

Biliary Secretion  This Lecture was supposed to be about Gastrointestinal Motility but the doctor switched it with the next lecture.  The Doctor at first was surprised by the low attendance of this lecture, so he took the attendance on some sheets and advised us to attend the lectures always.  This Lecture is easy and simple, so please enjoy!

Khalid Al-Qudsi

Let’s Start:  Bile is Produced by Liver cells (Hepatocytes) but the storage is in the gallbladder.  PH of bile ≈ 7.8 (Alkaline) - The alkalinity is very important; mostly it is due to the presence of bicarbonate.  Adult humans body produce 0.6 to 1 liter of bile daily (About 1 liter or less)  The importance of the bile secretion is very important for two reasons : 1. It contains bile salts, these salts -as we will see later on when we describe digestion and absorption of fats- are very important for digestion and absorption of fats and without bile the digestion and absorption of these fats will be very little, and there are another component which are very important, and within fat, the fat-soluble vitamins, they need bile salts (or acids) to be absorbed also. (vitamin A,K,E,D) 2. It is a route for excretion (mostly the bilirubin) and bilirubin as we will see is a waste product and it is excreted through the bile.

 What about the composition of the bile?

-

Mostly water, Bile salts (acids), fatty acids, lecithin (but little), Electrolytes (mostly sodium, chloride, bicarbonate, calcium, potassium , Bile pigments (bilirubin) –don’t confuse between bile pigments and bile salts-, Cholesterol.

 The story of secretion is similar to pancreatic secretion, the initial secretion is coming from Hepatocytes and then there will be modification and the modification will be in two stages, the first stage in the bile canaliculi(small canaliculi), the second stage of modification will occur inside the Gallbladder -as we will see just in few minutes-, So initial secretion coming from Hepatocytes consisting of bile acids (because bile acids is formed inside the liver cells), cholesterol (an extra amount of cholesterol is excreted through bile), bilirubin (as a waste product) and other organic substances.  This initial secretion goes to the bile canaliculi and then in the bile canaliculi there is a modification (there is secretion of watery solution composed of electrolytes and water) and this secretion of watery fluid containing electrolytes is added by epithelial cells lining the Biliary ductules (the small ducts of the Biliary system) and it is under the effect of secretin hormone (responsible for more watery secretion from the pancreas and from the Biliary system), and this is the first modification.  This sentence is important, the initial secretion of the bile is stimulated by the bile acids in the blood, as we will see the bile acid is produced in the liver→ excreted in the bile→ goes to the intestine→ and from the intestine it will be reabsorbed to the blood, in the blood it has this function (stimulation of secretion of more bile acid from the Hepatocytes through the bile initial secretion)

 Where the bile will go?

- It has two destinations, either if it is needed, it is produced by the liver→ it will go directly through the hepatic duct → the common bile duct → the duodenum, but if there is no need for it, it will be stored in the gallbladder through the cystic duct.

-

Look here at the sphincter of oddi, if it is closed, we don’t need bile then the bile will be diverted to the gallbladder where it is stored, when we need this bile again, another hormone called Cholecystokinin (CCK) causing contraction of the gallbladder and at the same time relaxation of the sphincter of oddi → bile is going to duodenum.

-

Important note, the bile is continuously formed and secreted by the Hepatocytes (and this doesn’t mean the same magnitude, there is factors stimulate more secretion and production) and as we said, if it is needed it goes directly to the duodenum through the common bile duct, and if it is not needed the sphincter of oddi will be closed, the bile will be diverted to the gallbladder where it is stored until the need for it.

Bile in the gallbladder is concentrated through active absorption of sodium and secondary absorption of chloride and water, and the bile in the gallbladder can be concentrated 5-20 folds (times), it means that there is absorption of water and a little bit modification of electrolytes composition

-

(some electrolytes concentration will change a little bit increase and some will increase more) and this is the second modification.

Is this gallbladder bile concentration to preserve the volume?

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maybe, it seems logic, because for instance a person not eating fat (reminding you that fat is the most important factor to stimulate CCK) it means that 0.5 liter will go to the gallbladder and from the anatomy the capacity of the gallbladder is less than 0.5 liter so it will concentrate the bile to decrease the volume but it is mainly to increase the concentration because it seems that bile salts concentration is important.

-

So if the person is eating fatty food the concentration will be little and If the person is not eating fatty food the concentration will be more, because if is there CCK, the sphincter of oddi will be open and there will be no diversion to the gallbladder.

ď&#x201A;ˇ This comparison is just to give you an idea about the concentrations ( it is not important to remember all these things) :

-

At the beginning, in the liver bile it is mostly water (98%) but in the gallbladder it will decrease to 90%, the bile salts will be concentrated 6 times in the gallbladder, Lecithin will be concentrated 7 times, Sodium is

hardly changed (because it is absorbed with the absorption of water), Chloride will be decreased 4 times, Calcium is not absorbed at all, it is concentrated 4 to 5 times, Bicarbonate is absorbed and decreased 3 times, PH doesnâ&#x20AC;&#x2122;t change too much and this decreasing in PH is related to decreasing in bicarbonate concentration but still it is alkaline. ď&#x201A;ˇ Now, we will talk about the empting of the Gallbladder, we have two important factors, hormonal and Neuronal.

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Hormonal: through Cholecystokinin which is very important hormone, secreted from special cells as we had seen (I-cells in the duodenum), it is the most potent stimulus for causing gallbladder contraction, and as we said presence of fat in the duodenum will stimulate the secretion of CCK so fat is important for causing of gallbladder contraction and at the same time CCK must relax the sphincter of oddi.

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Neuronal: through Acetylcholine which is liberated through the autonomic nervous system (vagal nerve endings) and the enteric nervous system ending in the gallbladder having similar action to CCK (contraction of the gallbladder and this contraction is always associated with relaxation of the sphincter of oddi)

ď&#x201A;ˇ Bile acids and salts :

-

The substances in the bile actually they are bile acids, and these bile acids are formed from cholesterol, cholesterol is either coming from the diet or it is synthesized in the liver, and this cholesterol will be converted to bile acids, and these bile acids are have two forms (cholic acid and chenodeoxycholic acid) and these are the two forms which are produced by the liver cells from cholesterol. (50% cholic acid and 50% chenodeoxycholic acid)

-

Then there will be a conjugation of these bile acids, mostly with glycine which is of course an amino acid- and to lesser extent with taurine -synthesized from cysteine and methionine- , and then these conjugated bile acids are secreted into bile canaliculi where they bind with sodium and potassium forming bile salts, so the end result will be bile salts rather than bile acids (but these terms - the bile acids and bile salts- are sometimes the same because they will do the same action).

 Entero-hepatic circulation of bile salts:

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These bile salts are very important to our body as we have seen for fat absorption and digestion and reminding you that the liver capacity to form bile salts is limited so what is used in the intestine -to facilitate the digestion and absorption of fats- must be recovered in order to make less burden )‫ (عبء‬on the liver, i.e. if no bile salts is absorbed from the intestine after finishing their function, the body will suffer from less bile salts in the body and of course this will be reflected on the digestion and the absorption of fatty acids and so on, so we need entero-hepatic circulation to recycle these bile salts from the small intestine to the liver.

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Bile salts in the bile are delivered to duodenum through ampulla of vater.

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94% of the bile salts that performed their actions will be absorbed into the blood again from the small intestine (the terminal ileum-the same side of Vit. B12 absorption) and then these absorbed bile acids will be transported by the blood to the liver and re-excreted in the bile canaliculi. So only 5-6% will enter the colon to be excreted in the feces and lost, and this lost will be compensated by the newly formed bile salts in the liver.

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This diagram explains what I (The Dr.) have said, the liver forming bile salts and its amount is 0.2 g/day, then it will go to the duodenum and after finishing their function 94% will be absorbed in the terminal ileum to the blood and goes to the liver through portal system where it will be reused again and about 6% will be lost in the feces (0.2 g/day which is the same amount of newly formed bile salts in the liver).

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Another extra note about bile salts, their presence in the blood has two functions: 1. Inhibitory function, they inhibit bile acid synthesis, because logically if the bile acids are too much then we need to reduce the amount synthesized (Through –ve feedback mechanism).

2. Stimulatory function, stimulate release of the bile from the Hepatocytes into the bile canaliculi.  So bile acids in the blood inhibit the synthesis of bile acids through –ve feedback mechanism and stimulate the secretion of bile into bile canaliculi from the Hepatocytes.

 Bilirubin, reminding you that most of these points, I think you are familial with them from the HLS, e.g. in the catabolism of the hemoglobin.

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Bilirubin is a useless and toxic breakdown product of hemoglobin, i.e. it is a waste product, so we have to get rid of it, and this is done through the bile (the biliary system).

 Let’s talk about the story of from where the bilirubin is coming, coming from the hemoglobin, RBCs after finishing their life or function of carrying oxygen after 120 days in the circulation, eventually they will be destroyed, damaged and phagocytized by the reticuloendothelial system specially in the spleen and the liver, and within the phagocytes or macrophages whatever, RBCs will be damaged and hemoglobin will be liberated and at the same time the hemoglobin in the phagocytes will be broken into:

1. Globlin (a polypeptide) → catabolised to amino acids to be reused.

2. Pyrrole (4 rings) → biliverdin → bilirubin (released into Plasma).

3. Iron → recycled to be reused again to form new RBCs.  in some books they say that this bilirubin is water-insoluble and in other books they said that the solubility in water is less (slight) which is more accurate, so in the plasma -when bilirubin it is released form macrophages- , we need a carrier for it as a combination with albumin, and this type of bilirubin is called free bilirubin (unconjugated form)! Which is not clear because it is bound to albumin but if you compare it with another form which is the conjugated form which is water-soluble, and if you remember from HLS the free bilirubin gives you the indirect bilirubin because it gives an indirect result to the van den bergh test- and also called unconjugated bilirubin and the other form is the direct form (conjugated bilirubin) -because it gives a direct result to the van den bergh testFrom internet conjugated bilirubin , direct bilirubin bilirubin that has been taken up by the liver cells and conjugated to form the water-soluble bilirubin diglucuronide. indirect bilirubin , unconjugated bilirubin (Free) the lipid-soluble form of bilirubin that circulates in loose association with the plasma proteins.

-

-

Free bilirubin in the circulation will be absorbed by the liver cells (through hepatic cell membrane) and inside the Hepatocytes the conjugation process will take place, and conjugation is used to convert bilirubin from less soluble (insoluble in water) to more soluble form (or totally soluble in water) and this conjugation is mostly (80%) with glucuronic acid and this needs an enzyme which is glucuronyl transferase (this enzyme is found in smooth endoplasmic reticulum) so if this enzyme is not there (due to diseased Hepatocytes or the enzyme is absent congenitally) → the end result will be no conjugation and less direct form is present → less excretion of bilirubin so the bilirubin concentration in the blood will be increased .

Glucuronyl Bilirubin + glucuronic acid -------------------> bilirubin diglucuronide Transferase

-

So as we said 80% of bilirubin will be conjugated with glucuronic acid, 10% with sulfate and 10% with other substances so the majority of the end result will be bilirubin diglucuronide (or bilirubin glucuronide for simplicity)

-

The conjugated bilirubin is very soluble in water, so naturally some of this bilirubin will escape into the plasma, so in the plasma we have free bilirubin combined with albumin in addition to small amounts of conjugated bilirubin which is escaped from the liver cells, and both of them (the direct and the indirect bilirubin) are called Total bilirubin and its concentration is less than about 1 mg/deciliter and when it is more than 3 mg/dl it will give you jaundice (‫(اليرقان‬, yellowish pigmentation.

-

Conjugated bilirubin in Hepatocytes is actively transported into bile canaliculi and finally to small intestine (duodenum), so this conjugated bilirubin in the bile canaliculi either it will go to the gallbladder where it is stored or it will go directly to the duodenum, so the end result of the

conjugated bilirubin will go to the duodenum and then we have recycling of the conjugated bilirubin.  An important thing about movements of blood and bile, that they are opposite to each other, reminding you with the circulation through the liver, we have two types of the blood coming to the liver, arterial blood from the Hepatic artery and venous blood coming from the intestine through portal vein mixed here ( ) , as you know the bile is formed by the Hepatocytes and then secreted into the bile canaliculi, then the direction of flow of course will be to the bile duct opposite to the direction of the blood flow which is directed to the central vein.

 Let’s return back to the story of recycling of the conjugated bilirubin in the intestine :

-

The unconjugated bilirubin goes to the liver → conjugation in the liver → conjugated bilirubin goes to the duodenum through ampulla of vater.

-

In the intestine, it will be converted to urobilinogen -by the action of intestinal bacteria- , urobilinogen is a very soluble in water, so naturally some of these urobilinogen will be absorbed back to the circulation through the intestinal mucosa, and from the circulation 95% of the absorbed urobilinogen will goes to the liver where it will be re-excreted again into intestine (Enterohepatic circulation) and some will go to the kidneys where it is excreted as urobilin in the urine.

-

What is left from urobilinogen which is not absorbed, it will continue its travel, this urobilinogen will be converted by colonic bacteria to stercobilinogin, then the stercobilinogin will be oxidized to stercobilin when it faces outside (when the stool is excreted outside),and stercobilin will give a sort of brownish color of feces (if stercobilin is not present → the feces color will be white)

-

This circulation of urobilinogen to the intestine, to the liver again, is called Enterohepatic circulation, so Enterohepatic circulation we describe it for both the bile salts and bilirubin. And they are almost the same (94% of bile salts goes to the liver and 95 % of absorbed bilirubin goes to the liver!).

95%

5% Stercobilin Give the brownish color in the stool

The End ‫بالنهاية دكتور مخلد هنأ الجميع بعيد سعيد وان شاء هللا يعيدوا عالجميع بالصحة والنجاح‬ . ‫وإن شاء هللا الكل ناجح بهذا السيستم‬

At the end, Please forgive me for any mistakes! and happy Eid from me also and may Allah bless you all and I would like to thank all my friends for making my life such wonderful, you all have the same love in my Heart .

mohammed Al-Shlool

Saad Al-Deen

Suhaib Abu shhab

Qusai Tamemi

Imad hussain

Mohammed Abu shhab

Mohammed Asim

Abdulrahman Nuwedir

Bassam AlHasson

Hasan AlQusa'a

Gayth AlHorany

Faisal Helmi

Also I would Like to thank My family for supporting me always, really I love you very much .

Done By: Khalid Al-Qudsi

31 / 59 5/7 25

Physiology Gastric and Intestinal Motility Mokhallad Janabi Noor Abu-Farsakh & Basma Deeb Sunday, 13/11/2011

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Physiology - Lecture 5 Sunday, 13-11-2011 Done by: Noor & Basma

Gastric and Intestinal Motility The gastrointestinal motility means the contraction of muscles, and here weâ&#x20AC;&#x2122;re talking about the smooth muscles of the GIT. And as you know, the GIT is a tube that has two openings, and the food is moved through it by the contraction of those smooth muscles.

The smooth muscles are of the involuntary type, and they have sometimes what is called the intrinsic activity, and sometimes it is excited or inhibited by the nerve supply. And this nerve supply is coming from the autonomic nervous system, or through a self specialized system in the GIT, and it is called the enteric nervous system.

We have two sets of smooth muscles in the GIT. One of them is arranged into two layer; inner circular, and outer longitudinal. The other set of muscles is called the submucosal muscles which are few muscle fibers here and there.

The electrical activity of the GI smooth muscles If we want to bring the resting membrane potential to the threshold, we need to reduce the negativity. Usually the negativity of the smooth muscles is very small in comparison to skeletal muscles; it is about -56 mv. ď&#x201A;ˇ If the resting membrane potential value becomes more negative, then the muscle will be less excitable, and this can be done by epinephrine and by the sympathetic stimulation. ď&#x201A;ˇ If the resting membrane potential value becomes less negative, then the muscle will be more excitable because here we are bringing the resting membrane potential closer to the threshold. This can be done by acetylcholine and by the parasympathetic stimulation. Also stretching the smooth muscles will lead to the increment of their excitability. And in addition to this, some hormones may increase the excitability.

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There are two basic types of electrical waves in the GI smooth muscles: -

Slow waves.

Spike potentials.

Here we are talking about the electrical activity, not about the muscle contraction. So this electrical activity may or may not lead to muscle contraction. And when we are talking about the electrical activity, here we mean the changes in the resting membrane potential.

The figure above shows the types of these waves, so letâ&#x20AC;&#x2122;s see the characteristics of each one of them: The slow waves They are fluctuations in the membrane potential; increasing or decreasing the negativity (in the slides: around 10 mv up and down), but they are NOT real action potentials; they do not reach the threshold. Usually the slow waves are preparing the muscles for contraction. So, when the negativity becomes less; from -56 to -40, the spike may appear, and the spike may lead to action potential.

So, the slow waves may lead to the spike potential, and the spike potential may lead to the action potential. But the slow waves by themselves cannot bring the muscle to the threshold.

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These fluctuations of the membrane potential are caused by special cells called Cajal cells. These Cajal cells are similar to the pacemaker of the heart; they have a less membrane potential. And this membrane potential is fluctuating, so when these fluctuations occur, the slow waves will be the result.

Their frequencies vary; the slowest in the stomach (3 per minute), the highest in the duodenum (12 per minute), and in between in the ileum (8 per minute). You don’t have to remember the details, but you should know that it is the slowest in the stomach, and the highest in the duodenum.

And here when we say fluctuations, we mean the decrease in the negativity which is done by cations, and here it is due to the entry of sodium ions (Na+) inside. And they are NOT due to the calcium ions (Ca++) movement.

The spike potentials The spike potential is due to the calcium ions (Ca++) movement mainly, and these calcium ions may lead to the contraction.

These spike potentials appear when the negativity becomes less; from -56 to -40.

And remember from the MSS physiology lectures, that when calcium ions (Ca++) bind to calmodulin >> that will lead to the phosphorylation of the myosin light chain >> and that leads to the interaction between myosin and actin >> and consequently to the muscle contraction.

So the slow waves are simply alterations in the membrane potential, and the spike potential -if it is strong enough- may lead to the action potential.

There is another type of contractions; which is the tonic contraction.

The tonic contraction When we say tonic contraction, it means a sustained muscle contraction. So sometimes the GIT will go into a continuous contraction; for minutes or hours. So what are the characteristic features of this contraction?  It is found in some of the smooth muscles in the GIT.  It is NOT related to the slow waves.  Its intensity increases or decreases in magnitude.

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 It is caused by repetitive spike potentials and continuous action potentials which lead to continuous muscle contraction. Also some GI hormones may increase the muscle contraction. Also the continuous entry of calcium ions may lead to a continuous contraction which is the tonic contraction.

The enteric nervous system Let’s move to another part of the story of the motility. When we say motility, we mean smooth muscles on one side, and nerve fibers on the other side.

We have two sets of the nerve supply to the smooth muscles in the GIT; the autonomic nervous system (the sympathetic and the parasympathetic), and the enteric nervous system.

The enteric nervous system is very important because it regulates many GIT activities, and it has two plexuses as we’ll see.

What are the digestive processes that can be controlled by the nerves?

-

The motility.

The secretion.

The absorption.

The GI blood flow.

So, ALL these activities can be controlled by the sympathetic, the parasympathetic, and the enteric nervous systems.

We have two plexuses in the GIT in which the enteric nervous system (ENS) is found: 1) Myenteric plexus; it is also called Auerbach plexus.

2) Submucosal plexus; it is also called the Meissner's plexus.

Myentric pleuxs It is found between the longitudinal and the circular muscles. Because this plexus is located between the muscles, then logically it will affect the contraction of the muscles.

The Myenteric plexus (Auerbach) primarily controls the GI motility. It increases the tone of the GI muscle, the intensity and the rate of rhythmic contractions, and the Page 5 of 14

velocity of conduction of excitatory waves along the GI wall. And it inhibits the GI sphincters.

So from this description you can see that motility of the GIT will end in moving the material inside it from one place into another, and this is done by the contraction of the smooth muscles.

Submucosal plexus It is found in the submucosa, and thus affecting the blood flow, and the GIT secretions. It also controls the contraction of the submucosal muscle fibers (causing folding of mucosa).

And remember that this enteric nervous system can act by itself, or its activity can be altered through the activation of the autonomic nervous system; the sympathetic and the parasympathetic. So naturally, the activity of the Auerbach and Meissner's plexuses can be affected by the activity of the autonomic nervous system.

And as you can see, we have sensory neurons that are important in delivering the GI reflexes. And always when we talk about reflexes, then we have sensory fibers, integrating fibers, and motor fibers. So we need sensory neurons and they are found scattered in the enteric nervous system.

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And also we have many receptors; chemoreceptors, mechanoreceptors, osmoreceptors, and thermal receptors. The stimulation of these receptors will lead to these reflexes; either increasing or decreasing the activity of the GIT. And as we said, this enteric nervous system is a system by its own; it has a huge number of neurons (108 in the slides). It has sensory neurons, motor neurons and interneurones. So, ALL the types of neurons are found there.

So, the enteric nervous system (ENS) acts through reflexes originating: -

Locally.

Or impulses coming from the GIT to the spinal cord, and then back to the GIT. Or from the GIT to the brainstem, and then back to the GIT.

The major neurotransmitters in the enteric nervous system (ENS): 1) The major one is the acetylcholine. So if you increase the acetylcholine in the smooth muscles of the GIT, that will lead to: o Stimulation of smooth muscle contraction. o Increase in the GI secretions. o Release of GI hormones as we have seen in the stomach. o Dilatation of the blood vessels.

2) Epinephrine; it is usually inhibitory.

3) VIP (vasoactive intestinal peptide), it causes the relaxation of the sphincters and increases the intestinal secretion.

4) Serotonin increases the intestinal blood flow during digestion.

5) Substance P increases the contraction, and it is similar to acetylcholine.

6) Nitric oxide (NO) is a dilator, so it causes the relaxation of the smooth muscles in the blood vessels, and in the GIT it causes relaxation of the GIT smooth muscles. ** Substance P, it is called â&#x20AC;&#x153;Pâ&#x20AC;? because it is the substance of pain, but in this position it is not related to pain.

So, each one of these neurotransmitters either increases or decreases the activity.

The sympathetic nerve fibers innervating the GIT arise from the thoracic segment and part of the lumber; from T5 and down to L2 spinal fibers.

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The parasympathetic nerve fibers come from the cranial nerves: Glossopharyngeal and Vagus (mostly the vagus). The glossopharyngeal supplies the mouth and pharynx only. The vagus supplies the esophagus, stomach, small intestine, and first 1/2 of large intestine.

And there are sacral nerve fibers II, III, IV which supply the lower part of the GIT (cecum, colon, & rectum). [In the slides: they supply the second 1/2 of large intestine.]

Of course, parasympathetic stimulation increases ALL the GI activities: motor activity, secretion of hormones, and absorption.

Hormonal control of GI motility We have seen at the beginning that the smooth muscle of the GIT has a spontaneous activity (spike potentials or slow waves). It can be affected by stretching or by local hormones. Local hormones in GI motility are very important; some increase its activity and some decrease its activity.

These are some of the hormones acting on the motility of the GIT: Gastrin: It’s secreted from G cells in the antrum of the stomach. It’s important for gastric motility as it’s affecting the stomach mainly. It stimulates gastro-esophageal sphincter and promotes stomach emptying. So, it prevents regurgitation of material from stomach to esophagus, and at the same time, it promotes the evacuation or emptying of the stomach.

CCK: It increases contraction of gallbladder, inhibits sphincter of Oddi, and inhibits contraction of the stomach. So, it’s the opposite of gastrin. [Gastrin promotes stomach emptying while CCK slows stomach emptying.]

Secretin: It has a mild effect on the motility, but it can cause contraction of pyloric sphincter.

And we'll see that secretin will slow the emptying of the stomach.

So, secretin and CCK slow the emptying of the stomach.

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Gastric inhibitory peptide: From its name, it inhibits gastric contraction decreasing the motor activity of the stomach.

Motilin: It increases GI motility, and this motility is increased mainly during fasting hours; when you are not eating, still there is contraction in the GIT. Sometimes, it's called hunger pain. If you eat, then motilin secretion is decreased and this contraction will stop and hunger pain will be relieved.

VIP (Vasoactive Intestinal Peptide): It relaxes intestinal smooth muscle including the sphincters. This is important because we will see that during peristalsis we have contraction in one part and relaxation in another part. In order to make this relaxation, you need inhibitory neurons; these inhibitory neurons secrete VIP. So, this was an introduction to motility in general. Letâ&#x20AC;&#x2122;s move to contraction of the different parts of the GIT. We've already talked about swallowing, pharynx, and esophagus. Letâ&#x20AC;&#x2122;s move to motor activity of the stomach.

Motor functions of the stomach As far as stomach is concerned, we have three types of motor activity: 1- Storage: the stomach will store the received material from the esophagus in order to break it down and partially digest it, and then when it is converted to a suitable form, it will be delivered to the duodenum.

2- Mixing of food; mixing it with HCl, pepsin, etc.

3- Emptying of the stomach material to the small intestine.

Regarding storage: in order to make the stomach as a store, it has to be relaxed; and this relaxation can be done by two ways: 1. Receptive relaxation: we've talked about that; when there is peristalsis in the esophagus, the segment next to a contracted segment will be relaxed.

Page 9 of 14

2. Vagovagal reflex: it means that impulses from the stomach go to the brain stem, then back to the stomach (ALL this via the vagus nerve); this leads to relaxation or decrease of the tone of the smooth muscle of the stomach.

[Relaxation means accommodation of more material.]

Regarding mixing, we need to move the material. So, this mixing is similar to peristalsis; constrictor waves appear here and there, and these constrictor waves will shuffle the material from one place to another within the stomach. This is very important for mixing the material with the digestive juice.

Regarding emptying, itâ&#x20AC;&#x2122;s usually slow emptying; you donâ&#x20AC;&#x2122;t need to empty ALL the material at one time. It is very important to empty the stomach gradually in order to give a small amount to the duodenum. And this is done by opening of the pyloric sphincter (sometimes called pyloric pump).

We can divide the emptying of the stomach into 2 divisions: 1. Factors increasing the emptying: they are factors coming from the stomach itself. These factors include: - Distention (stretching): when there is distention, there is contraction and this contraction will increase the emptying of the stomach.

- Gastrin hormone: we have seen that gastrin increases the gastric emptying by increasing the contraction and enhancing the pyloric pump.

2. Factors decreasing the emptying: they are factors coming from the duodenum, so duodenal factors are inhibitory; they decrease the amount of material coming from the stomach.

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Figures on previous page may help.

These are the stomach and the duodenum. You can see that when material is delivered to the duodenum, it will affect either chemoreceptors or lead to secretion of secretin (hydrogen ion is important). So, when the material reaches the duodenum, secretin will be secreted plus some other hormones; these hormones will be carried by blood going to the stomach decreasing its activity and decreasing the emptying.

Also, fats, proteins, hyperosmolarity, and hypertonicity will lead to secretion of CCK and GIP (gastric inhibitory peptide). This will slow the emptying of the stomach.

Intestinal Movement We have two types of intestinal movement: 1. Peristalsis 2. Segmentation The aim of both is to mix the material with the digestive juice and aid in absorption.

In peristalsis, you have contraction in one place and relaxation in the part in front of it, and then contraction in the part which was relaxed. By this way, peristalsis will aim to move the material from one place to another place toward the anal part.

Segmentation is for mixing; some parts are in contraction phase and some are relaxed, and then after certain time they will alternate: those parts which were previously in contraction phase will be relaxed, and the parts in relaxation phase will contract. By this way, there will be mixing of material.

Note the difference between the two:

Page 11 of 14

We have factors stimulating peristalsis: 1. Distention: when there is distention, there is peristalsis.

2. Chemical or physical irritation: for instance, if there are irritating substances or increase in acidity, this will lead to increase in peristalsis 3. Parasympathetic stimulation: through acetylcholine.

The important thing about peristalsis is that it needs the presence of the enteric nervous system (myentric plexus); if the enteric nervous system is not there, peristalsis will be affected (very weak or absent).

Peristalsis is increased by CCK, gastrin, motilin and decreased by secretin.

Sometimes, we have a very strong peristaltic activity specially when there is irritation; this is called peristaltic rush. If the small intestine wall is irritated by infection, chemicals, or toxic food, this will lead to increase in peristalsis. When peristalsis is increased, this means that there is less time for material to be absorbed and this will lead to diarrhea.

Ileo-cecal valve From its name, it’s located between the ilieum and cecum, so material from the small intestine toward the large intestine is guarded by this valve. It’s very important because we’re talking about two places different from each other. Its function is to prevent material from moving from the cecum toward the ileum (backflow). At the same time, it allows the material from the ilieum to move toward the cecum. It remains slightly constricted and this slows emptying of ileal content into the cecum.

Relaxation of this valve occurs through what’s called gastro-ileal reflex. It means that impulses from the stomach through the vagus or myentric plexus reach the ileo-cecal valve [this happens especially when you are eating; you can feel that there is movement in the GIT]. These impulses lead to relaxation of the ileo-cecal valve and evacuation of material from the ileum toward the cecum. And this may explain why you have the desire to go to the toilet after eating; this is due to the gastro-ileal reflex through the opening of this valve.

Page 12 of 14

It can stand certain amount of pressure; if the pressure in the cecum is increased more than (60 cm H2O), it will lead to movement of material from the cecum to the ileum. In the cecum, there are a lot of bacteria, so this pressure may lead to increase in these bacteria in the ileum leading to abnormalities.

Distention of the cecum will increase the contraction of the ileo-cecal valve, so decreasing the emptying from the ileum to the cecum.

The paralytic ileus: the ileum, small intestine, or GIT become paralyzed. They found that if there is trauma to the intestine after abdominal surgery or irritation to the peritoneum, this will lead to paralysis of small intestine. This is done through stimulation of sympathetic nerve fibers which inhibit peristalsis.

These are reflexes regarding movement of material in the GIT: 1. Gastro-colic reflex: from its name, it’s from the stomach to the colon causing evacuation of colon.

2. Enterogastric reflex: from the small intestine to the stomach inhibiting gastric motility and secretions.

3. Colono-ileal reflex: from the colon to the ileum inhibiting emptying of the ileum.

Movement of Colon The material reaching the cecum contains very little absorbable material, so this part of the GIT is for evacuation. The first part of the colon is for mixing and the second part is for storage; which means that during movement of material through the large intestine, there is some mixing which aims to increase the absorption of water and some electrolytes. And the last part is for storage which means that when the material reaches this part, it is material to be evacuated outside.

As far as colon movement is concerned, we have this type of shape “haustration”. Of course, we have longitudinal smooth muscle and circular smooth muscle. The longitudinal muscle is called tinea coli. Contraction of circular muscle in one part and contraction of longitudinal muscle lead to this shape “haustration”. Haustration is the characteristic picture of the large intestine.

Page 13 of 14

Propulsive and storage movement is to evacuate (defecate) the material outside.

Propulsive movement is not occurring ALL the time; it occurs at certain times during the day (one to three times daily).

Propulsive movements are slow movements provided by haustrations formation.

And there are mass movements in order to evacuate the material (one to three times daily). They are increased by certain reflexes; one of them is called gastro-ileal reflex in order to open the ileal valve.

These movements are stimulated by gastro-colic and duodeno-colic reflexes which means impulses from the stomach to the colon or from the duodenum to the colon.

DONE!

Do not let your difficulties fill you with anxiety!

After ALL, it is in the darkest of nights that the stars shine most brilliantly :)

Page 14 of 14

42 / 59 6/7 20

Physiology Digestion in the GIT Mokhallad Janabi Dina Istaiti Tuesday, 15/11/2011

1

Digestion in the GIT Today we will talk about the digestion of materials inside gastrointestinal tract. The aim of this process is to break down the materials in the foodstuff into small absorbable units.

We have 3 types of substances in our food in general; carbohydrates, lipids and proteins. These are usually found in big molecules, so we have to break down these materials.

Digestion of carbohydrate The types of carbohydrates in our diet: - Starch (mainly): it is a polysaccharide; glucose polymer, that has the glucose molecules attached together by certain chemical bonds. And it has a plant origin like potatoes, bread and rice.

- Lactose: it is called the milk sugar (found in milk) and it is a disaccharide.

- Sucrose: (table sugar) it is also a disaccharide.

- Glycogen: (highly branched molecule) it is a glucose polymer, but it is from animal sources.

- Cellulose: unfortunately -as humans- we canâ&#x20AC;&#x2122;t digest it. But it can be digested for a very limited degree by some bacteria in the colon, and not by our enzymes.

What is the difference between starch and glycogen? They differ in the origin and in the type of side chains, but they are essentially a glucose polymer.

2

Carbohydrates digestion starts in the mouth because there we have αamylase; in this part of our system it is called ptyline. The optimal pH of it is about 6.7, so it is suitable to work in the mouth. But when it reaches the stomach if the pH becomes acidic, then the amylase’s action will be stopped.

The process of digestion of carbohydrate is called hydrolysis. So ptyline hydrolyzes starch into smaller units of: maltoses (disaccharides), maltotrioses (trisaccharides) and dextrin (glucose polymer similar to the starch but of smaller units; it is around 8 glucose molecules).

How much can we digest from carbohydrate in our diet by the salivary amylase? It is very limited; because the time available for the amylase to act on the food is very short during chewing and swallowing. So they found that only around 5% of starch will be hydrolyzed to maltose and other short glucose polymers.

This diagram shows a glucose polymer; glucose molecules attached by certain bonds. There are 2 types of bonds; the straight chain 1-4 linkage (between C1 and C4), and the branching linkage; 1-6 linkage.

As we have seen, the α- amylase’s optimal pH is around 7, so naturally, if it reaches the stomach and the media becomes acidic, then amylase’s action will be stopped. But usually when the food reaches the stomach it is packed in layers, so what is exposed first to the acidic medium is the peripheral part.

3

In other words, the most interior aspect of the swallowed food is not exposed to the hydrochloric acid when it first reaches the stomach, so there is a possibility for the amylase to work because the pH is still not very acidic, so this will give an extra time for the amylase to work.

But how much? Nobody knows! It depends on how much you ate, and on the speed of mixing of your food with HCL, but usually the amylase will digest about (10 to 30) % of carbohydrates. And if there is enough time, then the amylase will work more, and it will digest about (30-40) %. So the ptyline’s action continues until the pH drops to 4.

The next enzyme that acts on carbohydrates is the pancreatic amylase, it is exactly similar to the salivary amylase, but it is more powerful. If any starches or glycogens or polysaccharides are not digested by the salivary amylase, then they will be digested by the pancreatic amylase. So starch will be converted into maltose and small glucose polymers.

The pancreatic amylase is very powerful, its amount is maybe more, and the pH in the duodenum is very suitable for the pancreatic amylase to work. So for this reason, all the starches in the diet when they reach the jejunum, then they will be digested into smaller molecules, but they are still not in the absorbable form.

The last stage of carbohydrate’s digestion is done by what is called the intestinal villi brush border enzymes; these enzymes are attached to the enterocytes’ micro villi (in these finger-like projections in the small intestine). These digestive enzymes are:  Lactase; converts lactose into glucose & galactose.  Sucrase; converts sucrose into fructose & glucose.  Maltase; converts maltose into 2 glucose molecules.  Dextrinase; converts dextrin into glucose molecules.

Dextranase enzyme breaks the 1-6 linkage (between C1 and C6 in the next molecule).

4

All these forms; glucose, galactose and fructose are absorbable forms of carbohydrate.

Some notes about carbohydrates’ digestion - Naturally if there is a deficiency in these enzymes, for instance if lactase is deficient, then the lactose will not be digested, and it is not absorbable, so it will stay in the intestine. Similarly, sucrose and maltose, if sucrase is absent, then the sucrose will not be digested it will stay in the intestine, and it will affect the media inside the intestine and leads to diarrhea (because if these disaccharides are not digested, they will be fermented, and even if they are not fermented, they will attract water by osmosis).

- The commonest type of deficiencies is lactase deficiency. The lactose will be fermented, and this will produce gases and so on. This is called lactose intolerance; it means lactose can’t be tolerated.

- Cellulose is found in the human diet, and it is similar to starch, but it is a straight chain not a branched one. So as far as the human is concerned, we don’t have enzymes that digest cellulose. There is some digestion of cellulose in the colon by the colonic bacilli, but not by our enzymes.

Digestion of proteins We haven’t got enzymes for protein digestion in the salivary secretion. The digestion of proteins starts in stomach simply because there is a powerful proteolytic enzyme (pepsin) that breaks down polypeptide chains. Pepsin is secreted in an inactive form (pepsinogen), this pepsinogen can be converted easily by the hydrochloric acid into pepsin.

Pepsin acts on certain bonds; not all the bonds in the polypeptide. It hydrolyzes the aromatic amino acids like tyrosine, phenylalanine and

5

tryptophan, so it acts on these bonds that bind these aromatic amino acids with other amino acids.

When pepsin attacks a polypeptide, it will break it into smaller polypeptides which are called by different names according to the number of amino acids; peptone, proteoses and polypeptides.

We need HCL for the action of pepsin. If HCL is not there, then first of all the pepsinogen is not converted into pepsin. And if the media becomes alkaline, then pepsinâ&#x20AC;&#x2122;s action will stop. The optimum pH for its action is around 2 to 3.

How much does pepsin contribute to protein digestion?

About (10-20) % of digestion can be done by pepsin because we need to digest the protein into individual amino acids in order to absorb them.

Pepsin also digests the collagen fibers. These collagen fibers are important because they are forming the intracellular bondages between the cells, so in order to increase the surface area in which the pepsin works, you have to break down the food material into individual cells. And this is done by pepsin itself, so pepsin can digest collagen to expose elastin and gelatin; which are proteinaceous materials.

In the stomach there is another digestive enzyme that is called gelatinase.

From its name, it digests gelatin.

Then protein digestion will be completed in small intestine by stages.

First of all, there are 3 important proteolytic enzymes; trypsin, chymotrypsin and carboxypolypeptidase. They are secreted in an inactive form by the pancreas, and they will be converted into an active form when they reach the duodenum.

Trypsin and chymotrypsin are described as endopeptidases; they act on interior peptide bonds.

6

While the carboxypolypeptidase is considered as an exopeptidase. So as a result of the action of carboxypolypeptidase, we get free amino acids. It is responsible for the separation of amino acids at both ends of the polypeptide chain. But under the effect of trypsin and chymotrypsin we will not get individual amino acids, we get smaller polypeptides.

We have elastase; it is also important to break down the elastin.

Pepsin, elastase and gelatinase, these enzymes help in the separation of the cells, so this will make the action of the proteolytic enzymes (trypsin, chymotrypsin and carboxypolypeptidase) more effective because you increase the surface area on which these proteolytic enzymes act on.

We need an enzyme to activate these proteolytic enzymes, and this enzyme is called enterokinase. It is found in enterocytes (the epithelium of the small intestine which is called the brush border villi). So, in the first stage of activation of trypsin, chymotrypsin and elastase, we need the enterokinase.

Once the enterokinase acts on trypsinogen, this trypsinogen is converted into trypsin. This trypsin will act as an autocatalytic enzyme to break down trypsinogen into trypsin.

This active trypsin will also act on the inactive forms of other proteolytic enzymes; so it will convert chemotrypsinogen into chemotrypsin, procarboxypolypeptidase into carboxypolypeptidase, and pro-elastase into elastase.

Naturally, if the enterokinase is not there, then weâ&#x20AC;&#x2122;ll not be able to digest proteins properly, so it is very important. Enterokinase deficiency leads to protein malnutrition; because if there is no activation of trypsinogen and other proteases, then the protein digestion be disturbed; because the digestion of proteins in stomach is about 30%, and what is left must be done in small intestine.

7

As a result of the action of all these proteolytic enzymes, we will end up with these forms of products; individual amino acids which are absorbable, the dipeptides and the tripeptides also can be absorbable, but they also must be broken down into amino acids. And this breaking down occurs in the cytoplasm of the enterocytes which have peptidases inside them.

What is left are the RNA and the DNA. We have another set of enzymes for them, and they come from the pancreas. These enzymes are the ribonuclease (which acts on RNA) and the deoxyribonuclease (which acts on DNA). And under the effect of these enzymes, they will be converted into nucleotides.

Also there are other enzymes in the brush border that will digest the nucleotides into nucleosides and phosphoric acids. And then these nucleosides will be converted into pentose sugars (5 carbon atoms) and nitrogen bases; either purines or pyrimidines, and these can be absorbed.

Digestion of fat We only have the lipase. This lipase is secreted in many places; one is in the mouth which is the lingual lipase (not in salivary secretion) from special glands on the dorsum of the tongue which are called Ebner glands. And we have the gastric lipase from chief cells of the stomach.

These are important points about the lingual lipase: it acts on triglycerides, it is active in the stomach, and it is responsible for less than 10% of fat digestion.

The Doctor mentioned some points about the lingual lipase to distinguish between the students who are attending the lectures and those who arenâ&#x20AC;&#x2122;t.

These are very important points:

8

**First of all, it is produced by the Ebner gland; which is found in the dorsum of the tongue. Ebner glands secrete the lingual lipase, and then it acts on fats and triglycerides.

Usually, this lingual lipase acts on a special form of fat which is the “milk fat”. This lipase can penetrate the milk fat, so it can digest the fat droplets (globules) in the mouth; so it is important in newborns.

The other thing about the lipase that it doesn’t depend on bile salts (for the pancreatic lipase, we need bile salts) because the lingual lipase can penetrate easily the droplets of fat in the milk. Also it is active in stomach; it can act in the acidic media.** The gastric lipase is similar to the lingual lipase - some books mention it, while others ignore it- but still the gastric lipase is there. It is produced by chief cells, and it is active in the acidic media. It doesn’t need bile salts for its optimal enzymatic activity, and so on….

By the way, the lingual lipase will become helpful in the person who has a deficiency in the pancreatic lipase. So if pancreatic lipase is deficient completely, then the lingual lipase can compensate for it partially in the digestion of some fat.

Proper fat digestion occurs in the small intestine, this is done under the effect of the pancreatic lipase. It is produced in an active form -there is no need for activation- and it acts on triglycerides (because they can’t be absorbed; they are big molecules) and convert them into individual fatty acids and monoglycerides; and both of them can be absorbed.

The important thing about the lipase is that it is a water-soluble enzyme.

And because it is attacking fats, so naturally it will act on the surface of the fat droplet. And in order to make the lipid digestion efficient, you have to break down these fat droplets into smaller droplets to increase the surface area, so the lipase can act more efficiently. And this is done by the process of emulsification.

9

This emulsification can be assisted by bile salts. And although the movement of the intestine can break down the fat droplets into smaller ones, these fat droplets have tendency to reunite (coalesce) again. So in order to prevent this reunification, you need the bile salts. So bile salts are important in emulsification.

Bile salts have very unique characteristic features; they have 2 poles or 2 sides, one is water-soluble (hydrophilic) and the other is lipophilic (cholic acid). So there will be no tendency for these small fat droplets to reunite again.

The other thing about bile salts is that when the lipid materials are digested into fatty acids and monoglycerides, they must be carried individually, and this is done by bile salts. So bile salts make fat droplets miscible (mixable) in water.

They found that under the effect of emulsification of bile salts, the fat droplets will be broken down into very small substances; less than 1 micron in diameter and this will increase the surface area, and thus the lipase will work more efficiently.

We need another enzyme for the action of lipase, and this is the colipase enzyme. It is secreted by the pancreas in an inactive form (procolipase), and it must be converted into the active colipase to facilitate the attachment of the lipase to the fat droplet.

See the picture on the next page: this is the bile salt, and this is the colipase. The colipase will be inserted between bile salts, and then the lipase will use the colipase to attach to the surface of the bile salts.

10

The lipase will digest the lipid gradually to end up with fatty acids, monoglycerides, cholesterol, and fat-soluble vitamins and so on. And those will be carried by bile salts forming micelles.

Enterocytes contain a lipase enzyme that is similar to the pancreatic enzyme, but usually it is not active (not needed) because the pancreatic lipase is quite enough and it is very powerful.

Procolipase is converted into the active form (colipase) by trypsin, and it is found in the intestine.

There are other points about lipids. We have phospholipids and cholesterol esters. The enzymes that act on them are: ď&#x201A;ˇ Phospholipase enzyme; acts on phospholipids to form fatty acids and lysophospholipids (lysolecithin is one of them). ď&#x201A;ˇ Cholesterol esterase; acts on the cholesterol esters to form the free Cholesterol.

Then the free cholesterol, the fatty acids, and the lysolecithin can be absorbed.

The end DONE BY: Dina Istaiti 11

43 / 59 7/7 25

Physiology Absorption in GIT Mokhallad Janabi Batool Al-Saifi Thursday, 17/11/2011

Absorption

Physiology lecture # 7

NOTES : Usually when we talk about absorption we mean absorption from small intestine.

The bulk of absorption happens through small intestine, and little in the large intestine (water and electrolytes). And very little absorption occurs in the mouth as for certain drugs (Nitroglycerin).

 Always when we say absorption  we mean absorption from the surface.  More surface area  more absorption.  In the stomach  very little amount of alcohol can be absorbed as well as some drugs (aspirin) Absorption in the stomach is limited because of the lack of villi and the presence of tight junctions between the gastric epithelial cells.

This diagram shows how the small intestine is accommodated for absorption, and how much surface area is available  200 square meters and that's really huge.

Take a cylindrical piece (0.3 m2 )  with these folds it became (1 m2) = larger by three folds  with the villi (finger projections from the surface of the epithelium) it became (10 m2) 10 x  with the small micro villi it became (200 m2) 20 x  Surface area amplification.

Structure of the villi : These folds [villi] also called the valvulae conniventes.

You can see in this pic also the microvilli [brush borders], arterial blood, venous blood, and lymphatic vessels called (lacteal).

So In the anterior aspect of the villi ď&#x192; we have three sets of vessels which are ď&#x192; vein, artery and lymphatic vessel.

The idea of absorption ď&#x192; is to bring materials from the lumen to the capillary.

Some will go directly to lymphatic tissue (central lacteal), then eventually to the blood.

We want to concentrate on the cells in the crypts of the intestine. We have different types of cells:

Paneth cells: They provide host defense

against microbes in the small intestine. They are functionally similar to neutrophils. When exposed to bacteria or bacterial antigens, Paneth cells secrete a number of antimicrobial molecules into the lumen of the crypt, thereby contributing to maintenance of the gastrointestinal barrier, to make a balance between the normal flora and pathological flora. in other words , it will defend the intestine against invading microorganisms.

Enteroendocrine cells (APUD cells : Amine

Precursor Uptake Decarboxylase): as the name implies they are cells capable of amine precursor uptake and decarboxylation and of synthesizing and secreting polypeptide hormones.

Enterocyte cells: their life span is 2-5 days. In highly metabolic states, most of the approachable protein comes from these enterocytes.

Goblet cells: their sole function is to secrete mucin, which dissolves in water to form mucous. we need Stem cells for continuous regeneration ,for continuous formation of enterocytes, goblet cells, APUD cells and paneth cells.  So cells at the bottom are immature cells and at the top are the mature cells , when cells become mature they shed off and they are replaced by other cells.

Paneth cells  host defense Enteroendocrine cells  Amine Precursor Uptake Decarboxylase Enterocyte cells  proteins In highly metabolic states Goblet cells  secrete mucin Stem cells  continuous regeneration

digestion

The process of is to break down big molecules into small ones, and make these small molecules in contact with absorbing surface in the GIT; mouth, esophagus, small intestine, large intestine…

The absorbable forms of : carbohydrate are  the monosaccharide; fructose, galactose and glucose.

proteins are  amino acids , dipeptides and tri-peptides. fats are  fatty acids, cholesterol and monoglycerides.

1

Fat absorption

fats have no problem in penetrating the cell membrane of the enterocytes.

The products of fats digestion (monoglycerides, fatty acids, cholestrol) and lipid soluble vitamins  are carried by bile salts (micelles) to the surface of enterocytes, because these products are water insoluble they can penetrate the enterocytes without a carrier, they enter by diffusion and leave the bile salts behind.

So we need bile salts (micelles) to carry the end products; fatty acids & glycerol, from the lumen to the absorptive surface.

Last lecture we talked about agitation movement of the intestine plus the presence of bile salts this will produce small fat droplets "less than 1 micron in diameter.

These

micelles are very small in size (3-6 nanometers)

They carry the fat-end products and come in contact with the absorptive surface of the enterocytes. This allows them to pass between microvilli so their contact with absorptive surface is increased greatly.

They pass into enterocytes by simple diffusion leaving bile salts behind. But they must be carried by bile salts, otherwise they will coalesce again and they form a big particle. ď&#x192;¨ Miscelles will NOT fuse with the cell membrane of the enterocyte.

The fate of end-products of fat digestion inside enterocytes : We have two types of fatty acids ;

1- Small (short) and medium chain fatty acids like butter fats ď&#x192; Small fatty-acids containing less than 10-12 carbon atoms can penetrate to enterocytes and migrate directly to the interstitium and then to blood ď&#x192; with no esterification.

2- bigger molecules

(>12 carbon atoms) 

must be esterificated to make triglycerides, and covered by protein to make it water soluble in order to be carried in a water media and then it will be carried by lymphatic’s.

Esterification means that

fatty acids re-unite with the monoglycerides again forming triglycerides.

This figure shows what’s made by esterfication 

long chain fatty-acid, monoglycride, and cholesterol will pass inside, then we have a process of esterification done in the Endoplasmic Reticulum, triglycerides will be formed, protein will be formed by rough ER to cover these triglycerides in the Golgi apparatus.

This will form vesicles called chylomicrons, and they are large so they’ll pass out by exocytosis, then they get access to the interstitial then to lacteal vessels.

The fate of bile salts we need them to bring end products from the lumen to the surface, once they finish their job they’ll be used again, they’ll be re-absorbed by secondary active transport with Na+ once they reach the terminal ileum. So they’ll be reabsorbed to the liver, and recycled again…

Fatty acids are coming mainly from triglycerides and under the effect of lipase triglycerides are broken down to monoglycerides and fatty acids in order for them to pass by diffusion. inside the enterocyte cell they will be esterified , fatty acids will combine with monoglycerides forming triglycerides and for cholesterol there is also esterification . Here when triglycerides and cholesterol esters are formed they must be carried by chylomicrons.

Cholesterol is converted into cholesterol esters and forming chylomicrons.  Chylomicrons containing a center or a core and inside this center we have these triglycerides and cholestrol esters surrounded by phospholipids and proteins.

Chylomicrons are large fat drops up to 1

micron in diameter, they can be seen under the microscope especially the electron microscope.  Chylomicrons leave enterocytes by exocytosis, because they are big. Once the chylomicron gets access to the extracellular fluid or interstitial fluid they will be carried by the lymph.

Chylomicron structure and composition: Chylomicron is surrounded by protein and composed of:  Triglyceride 90%  Cholesterol 2%  Cholesterol esters phospholipids 3%  And what’s left is the apolipoprotein

 The chylomicron is a mean to carry triglycerides, cholesterol and fat-soluble vitamins to general circulation.  Chylomicrons disappear from the circulation in 1 hour by liver deposition

2

Sugar absorption

The absorbable forms of sugar are   Monosaccharide  Glucose  Galactose  Fructose  Pentose.

Glucose and galactose 

are absorbed to entrocytes by secondary transportation with Na+

As you can see in this picture above  there is a carrier and this carrier in order to work it must be attached to sodium. Active transport of sodium occurs at the basolateral aspect of the enterocytes reducing sodium concentration inside enterocytes. This energizes the co-transportation of glucose and sodium into enterocytes.  Na+ moves from the lumen to the enterocyte with its concentration gradient.  Glucose moves from the lumen to the enterocyte against its concentration gradient.

So glucose  concentration increases inside the enterocytes then it is transported to the interstitial tissue by facilitated diffusion (from high concentration to low concentration).

In order to make this more active  must form a concentration gradient for sodium and this is done by sodium-potassium pump at the basolateral aspect. The more the sodium concentration gradient difference, the more active this transportation will be.

In clinical practice, giving glucose with Na+ is useful in cases of diarrhea, as it helps in moving Na+ to the inside NOTE: Insulin has no effect on Na-glucose co-transportation.

Fructose absorption  Fructose is different from glucose and galactose; it is carried by facilitated diffusion from the beginning.

Fructose doesn't need sodium in order to be absorbed.

It needs a carrier protein and this carrier will bring fructose from high concentration into low concentration (fructose moves with its concentration gradient).  so we must have this concentration gradient otherwise this carrier will not work That's why absorption of fructose is not efficient as glucose absorption. Because glucose is carried against concentration gradient but fructose is with the concentration gradient.

But  most of the fructose which is absorbed, before it can be carried outside it will be

phosphorylated to glucose, so the end result of fructose actually will be converted into glucose

for those who think eating fructose instead of glucose will help them to lose weight, they are wrong; Because fructose will be absorbed and directly phosphorylated into glucose, so the concentration of fructose is getting less, this will lead to more diffusion of fructose from the lumen to the enterocytes, until there’s no more fructose in the lumen !

NOTE: Concentration of Na+ must be high in the lumen of the intestine to facilitate the absorption of glucose and galactose.  If for a pathological reason Na+-glucose co-transportation is not working  glucose will not be absorbed and severe diarrhea will result.

Pentose is absorbed by simple diffusion.

3

Protein absorption

is similar to glucose and galactose absorption; Using the sodium concentration gradient but with a different carrier.

The absorbable forms of proteins in small intestine :  Individual amino acids : o Neutral amino acids o Basic amino acids o Acidic amino acids  Dipeptides  Tripeptides

1.

Amino acids absorption

We have 20 types of amino acids, they are absorbed by cotransportation with Na+ to the enterocytes, then will be carried by facilitated diffusion to the interstitial, then to the blood.

On the luminal surface of the enterocytes we have

many Na+ dependent amino acids transporters, these transporters bind to amino acids after binding to Na+.  Amino acid absorption depends on electrochemical gradient of Na+ across the luminal border.

At the basolateral border of the enterocytes  amino

acids are exported from enterocytes into blood through carriers (transporters) which are not dependent on sodium gradient.

NOTE: Few amino acids are transported into interior of the enterocytes by facilitated diffusion

2.

Di-peptides and tri-peptides abs.

They are absorbed by a mechanism similar to that of amino acids (carriers use H+ instead of Na+).

Large proteins (peptides)  are not absorbed except in special circumstances especially in neonates, where large peptides (immunoglobulin’s antibody) can be absorbed from colostrum in the early days of life. (the mother produces colostrum directly after delivery and this colostrum is yellowish rathar than white milk, and it contains alot of immunoglobulins and the neonate has the ability to absorb these immunoglobulins although they are very big molecules and this is good for the immune system of the neonates).

The figure next page illustrates the whole process of amino acids, di-peptides and tri-peptides absorption

Free amino acids  can be transported through carrier mediated transport and some by facilitated diffusion  They are carried with Na+

Di-peptides and tri-peptides  are carried by H+ instead of Na+  and inside the enterocyte cell we have intracellular peptidases that will break down di-peptides and tri-peptides into amino acids, so the end result in the capillary will be amino acids only.

If large peptides are not digested  we have another chance to digest them by peptidases in the brush border so they will be converted to di-peptides and tri-peptides and they will be transported by a carrier inside the cell in order to be digested by intracellular peptidases

Vitamins absorption

4

We have two types of vitamins  water-soluble vitamins and Fat-soluble vitamins. 

Water soluble vitamins are absorbed with Na+ (secondary active transport "cotransport") in the upper parts of the small intestine.

We have special type for absorption of vitamin B12  We need the presence of the intrinsic factor secreted by parietal cells of gastric glands. and this absorption occurs in the terminal ileum. 

Fat-soluble vitamins  need the presence of lipase enzyme and bile salts

5

Calcium absorption

Calcium absorption takes place in the upper part of the small intestine Our system cannot absorb all the calcium ingested  only 30-80% of ingested calcium is absorbed Calcium is transported by active transport to the enterocytes  then it binds with (calcium binding protein) and this is induced by the active form of vitamin D.  Vitamin D also induces the formation of carrier proteins at the basolateral aspect of the enterocytes (to move calcium out of enterocytes).

So somehow, calcium binding protein is essential to prevent excess free Ca inside the enterocytes by inducing formation of carrier proteins. and also they induce the absorption of more Ca to the enterocytes by concentration gradient without increasing the free Ca inside.

NOTE: Calcium absorption is decreased by oxalate and phosphate "forming insoluble salts with Ca" and is increased by proteins

6

Sodium absorption

20-30 gm of Na+ is secreted to the lumen of the intestine (pancreatic secretions) + 5 gm of daily ingested Na+  99.5% of those are absorbed efficiently and only 0.5% is lost in the feces.

We have many forms of Na+ transportation  diffusion, active transport, co-transportation ..

NOTES : most of the sodium inside the intestine is not from our diet, it is coming from fluids which are secreted from the intestine.

Some of the sodium is absorbed with sugar and amino acids in the small intestine  Sodium can be absorbed by creating electrochemical gradient across the luminal border and this is done by active transport of Na+ at the basolateral border of the enterocytes so by diffusion sodium can move from high concentration to low concentration

Diffusion is done by the action of Na+/K+ pump which decreases Na+ concentration in the enterocytes, leading to more Na+ diffusion form the lumen to the enterocytes. this is done by active transport of Na at the basolateral border of the enterocytes.  In the large intestine, Na+ is also absorbed actively (Absorption of Na in the colon is increased by Aldosterone)

7

Chloride absorption

Chloride follows the absorption of Na+  When Na+ is absorbed from the lumen  the chyme becomes negative in respect to the Paracellular space, and therefore chloride moves along this electrical gradient The immature enterocytes in crypt of Lieberkühn secrete Na+ and Clwhich can be reabsorbed by the mature cells in the villi.

The channels through which Cl- is secreted  are regulated by cAMP. and they found that the activity of this cAMP is increased when there is cholera toxins. If a person has cholera, it will produce toxins and these toxins will increase the activity of cAMP causing large amount of Cl- and Na+ secretion into the lumen and alot of water will follow them causing severe diarrhea. and this explains why in cholera we have watery diarrhea.

8

Bicarbonate absorption

Absorption of HCO 3 happens indirectly through combination of HCO-3 with H+ to form H 2 CO 3 under the effect of carbonic anhydrase. and then dissociation of carbonic acid to form water and CO 2 1) HCO-3  gets into the lumen from pancreatic secretion, stomach secretion, Brunner cells ..

2) H+  is co-transported to the lumen 3) HCO-3  binds with H+ in the lumen to form CO 2 + water 4) CO 2  is diffused easily to the enterocytes and binds again with water to form HCO 3 + H+

HCO-3 is secreted from ileum and colon through exchange with ClH+ ions in the small intestine  are secreted through exchange with Na+

Water absorption

9

Water is absorbed by osmosis, there is no way to absorbed water other than osmosis, this is associated with absorption of nutrients and electrolytes (concentration gradient) Huge amount of water is absorbed  2 liters ingested plus 7 liters secreted from the GIT = 9 liters/day of water enter the GIT. All are absorbed except about 100 ml excreted in the feces.  There is a concentration gradient between the lumen and the paracellular space so water will move through osmosis  Water movement is due to differences in osmolarities Water absorption in the colon is associated with the active absorption of Na+ by epithelial cells of the colon

Absorption in the

large intestine

1500ml of fluid and chyme passes from the ileum to the colon through the ileo-cecal junction daily.

Almost all water is absorbed , leaving only 100 ml to be excreted with the feces. o proximal part of the intestine  is for absorption o distal part  is mainly for storage  Absorption of Na+ is very efficient especially in the presence of aldosterone hormone, and this Na+ is actively absorbed against its concentration gradient As we have said Cl- follows Na+ movement and water follows Cl- and Na+ movement Cl-  is also absorbed in exchange with HCO 3 that is secreted into the colon for neutralization of acids that’s produced in the colon by the action of bacteria.

Colonic bacteria can produce vitamin K, thiamine riboflavin, and vitamin B

B12

12 ,

this

isn’t efficient for humans because it can’t be absorbed from the large intestine.  absorption happens in the ileum in presence of IF) and this colonic bacteria can digest some sorts of cellulose

(B12

Composition of

feces

30%  dead bacteria 10%-20%  inorganic material 10%-20%  fats 30%  undigested roughage or fibers 2%-3%  protein The Color of the stool  is due to the presence of stercobilin The Odor  is due to presence of indol, skatole, mercaptans and H 2 S

About the Exam :  There are no questions about the discussion cases in the exam, but there will be marks for the attendance.  About the introductory case; there will be two questions in the mid exam and another two in the final exam.

The End

Batool Adnan Saify