Human Respiratory System Quiz
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Questions and Answers

What percentage of forced expiratory volume (FEV1) does the right lung account for?

  • 45%
  • 55% (correct)
  • 60%
  • 50%

    • What is the approximate total alveolar surface area of the lungs?

  • 60-70 m2
  • 50-60 m2
  • 70-85 m2 (correct)
  • 90-100 m2

    • What is the anatomical dead space volume for conducting airways?

  • 100 ml
  • 150 ml (correct)
  • 200 ml
  • 250 ml

    • How many bronchopulmonary segments are in each lung?

    <p>10 segments</p> Signup and view all the answers

    Which of the following statements about the trachea is true?

    <p>It ranges from the larynx to the primary bronchi.</p> Signup and view all the answers

    What role does the trachealis muscle serve?

    <p>Fill gaps in tracheal rings.</p> Signup and view all the answers

    How does oxygen requirement during exercise compare to quiet breathing?

    <p>It is higher during exercise.</p> Signup and view all the answers

    What is the purpose of the planes of connective tissue in bronchopulmonary segments?

    <p>To separate segments functionally.</p> Signup and view all the answers

    What is the length of the human trachea?

    <p>10 to 15 cm</p> Signup and view all the answers

    Which structure is innervated by the vagus nerve?

    <p>Trachealis muscle</p> Signup and view all the answers

    What separates the left vagus nerve from the trachea?

    <p>Arch of the aorta and its branches</p> Signup and view all the answers

    Which statement about the bronchopulmonary segments is true?

    <p>They are independent units with their own blood supply.</p> Signup and view all the answers

    What is the primary function of the pleura?

    <p>To establish a slippery surface for lung movement</p> Signup and view all the answers

    Which structure is in immediate contact with the right side of the trachea?

    <p>Right vagus nerve</p> Signup and view all the answers

    What pattern is typically observed in the arrangement of the lung hila?

    <p>Arteries above, bronchus at the back, veins in front and below</p> Signup and view all the answers

    What distinguishes the right main bronchus from the left main bronchus?

    <p>The right main bronchus is shorter, wider, and more vertical.</p> Signup and view all the answers

    What supplies the trachea with blood?

    <p>Inferior thyroid and bronchial arteries</p> Signup and view all the answers

    What type of blood does the bronchial artery carry?

    <p>Oxygenated blood only</p> Signup and view all the answers

    What feature is characteristic of the anterior border of the lung?

    <p>It has an angular notch on the left side.</p> Signup and view all the answers

    Which structure primarily drains the venous blood from the bronchial arteries?

    <p>Pulmonary veins</p> Signup and view all the answers

    Which of the following is NOT a function of saliva?

    <p>Digesting proteins</p> Signup and view all the answers

    What does saliva contain that helps destroy bacteria?

    <p>Thiocyanate ions and proteolytic enzymes</p> Signup and view all the answers

    Salivation can be inhibited by sympathetic stimulation.

    <p>True</p> Signup and view all the answers

    What is the average output of saliva per day?

    <p>1000-1500 ml</p> Signup and view all the answers

    What is the role of kallikrein in salivation?

    <p>It causes vasodilation and increases salivary secretion.</p> Signup and view all the answers

    The lower oesophageal sphincter is controlled by the _____ nerve.

    <p>vagus</p> Signup and view all the answers

    The upper oesophageal sphincter is under voluntary control.

    <p>False</p> Signup and view all the answers

    What is the primary composition of mucus secreted in the gastrointestinal tract?

    <p>Water, electrolytes, and glycoproteins</p> Signup and view all the answers

    What condition can result from dysfunction of the lower oesophageal sphincter?

    <p>All of the above</p> Signup and view all the answers

    Aspiration pneumonia develops when foreign materials enter the _____ tree.

    <p>bronchial</p> Signup and view all the answers

    What is the role of the vagovagal reflex in the stomach?

    <p>It allows stomach muscle relaxation in response to distension.</p> Signup and view all the answers

    Which of the following are main functions of the gastrointestinal tract?

    <p>Ingestion</p> Signup and view all the answers

    What type of muscle forms the lower esophageal sphincter?

    <p>Smooth muscle</p> Signup and view all the answers

    The external anal sphincter is made of striated muscle.

    <p>True</p> Signup and view all the answers

    What percentage of total pancreatic enzyme secretion is accounted for by the cephalic phase?

    <p>20%</p> Signup and view all the answers

    What is the primary function of interstitial cells of Cajal?

    <p>Create bioelectrical slow wave potential</p> Signup and view all the answers

    During which phase does secretin primarily stimulate pancreatic secretion?

    <p>Intestinal phase</p> Signup and view all the answers

    The primary hormone secreted by G cells of the gastric antrum is ______.

    <p>Gastrin</p> Signup and view all the answers

    What are the three main stimuli for pancreatic secretion?

    <p>Acetylcholine, Cholecystokinin, Secretin</p> Signup and view all the answers

    Bile is produced by the gallbladder.

    <p>False</p> Signup and view all the answers

    Which of the following hormones inhibits gastric acid secretion?

    <p>Gastric inhibitory peptide</p> Signup and view all the answers

    What is the primary function of bile?

    <p>Fat digestion and absorption</p> Signup and view all the answers

    Calcium influx through channels in smooth muscle membranes dictates action potential generation in the gastrointestinal tract.

    <p>True</p> Signup and view all the answers

    What is the primary precursor of bile salts?

    <p>Cholesterol</p> Signup and view all the answers

    What is xerostomia?

    <p>Dry mouth</p> Signup and view all the answers

    Cirrhosis can result from chronic alcoholism.

    <p>True</p> Signup and view all the answers

    The primary site of secretion for cholecystokinin is the ______.

    <p>duodenum</p> Signup and view all the answers

    Which division of the autonomic nervous system is primarily involved in stimulating gastrointestinal activity?

    <p>Parasympathetic</p> Signup and view all the answers

    Match the following liver functions with their descriptions:

    <p>Filtration and storage of blood = Removes toxins and stores nutrients Metabolism of carbohydrates = Regulates blood glucose levels Formation of bile = Aids in fat digestion Detoxification = Cleans the blood of drugs and hormones</p> Signup and view all the answers

    Match the following hormones with their functions:

    <p>Gastrin = Stimulates gastric acid secretion Secretin = Stimulates pancreatic bicarbonate secretion Cholecystokinin = Stimulates pancreatic enzyme secretion Gastric inhibitory peptide = Stimulates insulin release</p> Signup and view all the answers

    Hepatic cells produce ___ to remove ammonia from the body fluids.

    <p>urea</p> Signup and view all the answers

    Which vitamin is essential for the formation of most plasma proteins in the liver?

    <p>Vitamin K</p> Signup and view all the answers

    What indicates jaundice?

    <p>Yellowish tint of body tissues</p> Signup and view all the answers

    What are the three major sources of carbohydrates in the diet?

    <p>All of the above</p> Signup and view all the answers

    Which enzyme in saliva hydrolyzes starch into maltose?

    <p>Ptyalin (alpha-amylase)</p> Signup and view all the answers

    Where does most protein digestion occur?

    <p>Upper small intestine</p> Signup and view all the answers

    Pepsin is active at a pH of 5.

    <p>False</p> Signup and view all the answers

    What is the main function of bile in fat digestion?

    <p>Emulsification</p> Signup and view all the answers

    ___ are secreted by the pancreas to aid in fat digestion.

    <p>Lipases</p> Signup and view all the answers

    What does the first-pass effect refer to?

    <p>Reduction of drug concentration before it reaches systemic circulation</p> Signup and view all the answers

    Which statement is true regarding CYP3A4?

    <p>It is very common in drug metabolism.</p> Signup and view all the answers

    Match the following ions with their absorption characteristics:

    <p>Calcium ions = Actively absorbed, regulated by vitamin D Iron ions = Actively absorbed from the small intestine Sodium ions = Transported with glucose Water = Transported through osmosis</p> Signup and view all the answers

    What is the primary function of enterochromaffin-like cells (ECL cells)?

    <p>To secrete histamine</p> Signup and view all the answers

    Where are gastrin cells (G cells) located?

    <p>In the pyloric glands in the antrum</p> Signup and view all the answers

    What stimulates enterochromaffin-like cells to secrete histamine?

    <p>Gastrin</p> Signup and view all the answers

    The main driving force for HCl secretion by parietal cells is the ______.

    <p>H+-K+ ATPase</p> Signup and view all the answers

    Which components are secreted in the pancreatic juice?

    <p>All of the above</p> Signup and view all the answers

    Acidification of the duodenal lumen stimulates the release of secretin.

    <p>True</p> Signup and view all the answers

    What does pepsinogen activate into?

    <p>Pepsin</p> Signup and view all the answers

    Which hormone is primarily responsible for stimulating appetite?

    <p>Ghrelin</p> Signup and view all the answers

    What is the role of intrinsic factor in vitamin B12 absorption?

    <p>It binds to vitamin B12 to form a complex that is resistant to digestion.</p> Signup and view all the answers

    Cholecystokinin is released in response to free fatty acids and certain amino acids.

    <p>True</p> Signup and view all the answers

    Brunner’s glands secrete large amounts of alkaline mucus in response to ______.

    <p>tactile or irritating stimuli</p> Signup and view all the answers

    What are the main functions of the gastrointestinal tract?

    <p>Ingestion, mastication, propulsion, secretion of digestive juices and hormones, digestion, absorption, excretion, and defense against pathogens.</p> Signup and view all the answers

    Which of the following muscle types are involved in sphincters?

    <p>Striated muscle</p> Signup and view all the answers

    The gastrointestinal smooth muscle functions as a syncytium.

    <p>True</p> Signup and view all the answers

    The myenteric plexus controls the _____ contractions.

    <p>GIT</p> Signup and view all the answers

    What are interstitial cells of Cajal responsible for?

    <p>Creating the bioelectrical slow wave potential that leads to the contraction of smooth muscle.</p> Signup and view all the answers

    What stimuli cause the secretion of Gastrin?

    <p>All of the above</p> Signup and view all the answers

    Where are the secretions of Cholecystokinin produced?

    <p>I cells of the duodenum.</p> Signup and view all the answers

    Norepinephrine excites gastrointestinal activity.

    <p>False</p> Signup and view all the answers

    Xerostomia refers to a dry _____ due to reduced salivary flow.

    <p>mouth</p> Signup and view all the answers

    Which type of muscle change occurs during swallowing?

    <p>Contraction of striated muscles</p> Signup and view all the answers

    What is the primary role of saliva?

    <p>Cleansing the mouth, lubricating and protecting the oral cavity, dissolving food chemicals, and moistening food.</p> Signup and view all the answers

    What are some functions of saliva?

    <p>All of the above</p> Signup and view all the answers

    What ion is secreted actively in saliva?

    <p>K+</p> Signup and view all the answers

    The sympathetic nervous system significantly decreases the salivation rate.

    <p>True</p> Signup and view all the answers

    Which part of the nervous system primarily stimulates salivation?

    <p>Parasympathetic nervous system</p> Signup and view all the answers

    The average output of saliva per day is _______.

    <p>1000-1500ml</p> Signup and view all the answers

    What is the role of kallikrein in salivation?

    <p>Causes vasodilation for gland nutrition</p> Signup and view all the answers

    What can cause aspiration pneumonia?

    <p>All of the above</p> Signup and view all the answers

    What type of food does the lower oesophageal sphincter respond to?

    <p>Chyme</p> Signup and view all the answers

    The stomach functions include digestion and absorption of carbohydrates.

    <p>False</p> Signup and view all the answers

    Match the following types of cells in the gastric glands with their secretions:

    <p>Mucous neck cells = Mucus Peptic/chief cells = Pepsinogen Parietal/oxyntic cells = HCl and intrinsic factor Surface mucous cells = Viscid mucus</p> Signup and view all the answers

    What is gastroparesis?

    <p>Delayed gastric emptying</p> Signup and view all the answers

    Hiatal hernia is when the stomach bulges up into the chest through the hiatus.

    <p>True</p> Signup and view all the answers

    What is the primary function of enterochromaffin-like cells (ECL cells)?

    <p>To secrete histamine</p> Signup and view all the answers

    What hormone is secreted by G cells in the pyloric glands?

    <p>Gastrin</p> Signup and view all the answers

    Which of the following is a stimulus for ECL cells to secrete histamine? (Select all that apply)

    <p>Gastrin</p> Signup and view all the answers

    What is the main driving force for HCl secretion by parietal cells?

    <p>H+-K+ ATPase</p> Signup and view all the answers

    Match the following digestive hormones with their primary function:

    <p>Gastrin = Stimulates secretion of gastric acid CCK = Stimulates secretion of pancreatic enzymes Secretin = Promotes secretion of bicarbonate from pancreas Ghrelin = Stimulates appetite</p> Signup and view all the answers

    What is pernicious anemia caused by?

    <p>Lack of intrinsic factor and vitamin B12</p> Signup and view all the answers

    Helicobacter pylori infection is asymptomatic.

    <p>True</p> Signup and view all the answers

    What is the role of intrinsic factor?

    <p>To bind vitamin B12 for its absorption in the ileum</p> Signup and view all the answers

    Bicarbonate ions are secreted into the pancreatic ductules to _________ gastric acid.

    <p>neutralize</p> Signup and view all the answers

    Cholecystokinin stimulates the release of bile.

    <p>True</p> Signup and view all the answers

    What happens to trypsinogen when it enters the intestinal tract?

    <p>It is activated to trypsin by enterokinase.</p> Signup and view all the answers

    What can happen as a result of severe damage or blockage of the pancreas?

    <p>Acute pancreatitis</p> Signup and view all the answers

    What occurs during the hydrolysis of triglycerides?

    <p>Fat-digesting enzymes return three molecules of water to the triglyceride molecule.</p> Signup and view all the answers

    Which of the following enzymes are involved in carbohydrate digestion? (Select all that apply)

    <p>Pancreatic Amylase</p> Signup and view all the answers

    Pepsin is active at a pH of 5.

    <p>False</p> Signup and view all the answers

    What percentage of pancreatic enzyme secretion occurs during the cephalic phase?

    <p>20%</p> Signup and view all the answers

    Which of the following is NOT a source of carbohydrates in the diet?

    <p>Triglycerides</p> Signup and view all the answers

    The end products of fat digestion are free _____ and _____ acids.

    <p>fatty, monoglyceride</p> Signup and view all the answers

    Which hormone is primarily responsible for stimulating pancreatic secretion during the intestinal phase?

    <p>Secretin</p> Signup and view all the answers

    What are valvulae conniventes?

    <p>Folds in the small intestinal mucosa that increase the surface area of the mucosa.</p> Signup and view all the answers

    Cholecystokinin is secreted when food enters the upper jejunal mucosa.

    <p>False</p> Signup and view all the answers

    What does the first-pass effect refer to?

    <p>The metabolism of a drug before it reaches systemic circulation.</p> Signup and view all the answers

    What is the main function of bile acids during digestion?

    <p>Emulsification of fats</p> Signup and view all the answers

    What is the precursor of bile salts?

    <p>Cholesterol</p> Signup and view all the answers

    What are DMEs?

    <p>Drug metabolising enzymes.</p> Signup and view all the answers

    The liver is responsible for the formation of _______ factors.

    <p>coagulation</p> Signup and view all the answers

    Which of these factors can affect biotransformation?

    <p>All of the above</p> Signup and view all the answers

    Cholera toxin leads to fluid retention in the body.

    <p>False</p> Signup and view all the answers

    Match the following liver functions with their descriptions:

    <p>Filtration = Cleanses the blood from toxins and bacteria Metabolism = Processes carbohydrates, proteins, and fats Bile formation = Produces bile for fat digestion Storage = Stores vitamins and iron</p> Signup and view all the answers

    Cirrhosis usually results from chronic alcoholism or fat accumulation in the liver.

    <p>True</p> Signup and view all the answers

    What condition occurs when there is high plasma ammonia concentration?

    <p>Hepatic coma</p> Signup and view all the answers

    Which substances are typically excreted in bile?

    <p>Bilirubin</p> Signup and view all the answers

    In haemolytic jaundice, bilirubin is mostly unconjugated.

    <p>True</p> Signup and view all the answers

    What is the primary role of the hepatic macrophage system?

    <p>Cleansing the blood</p> Signup and view all the answers

    Study Notes

    Lungs

    • The right lung is larger than the left and weighs more, despite being shorter, responsible for 55% of the forced expiratory volume (FEV1) in one second.
    • The lungs' primary role is ventilation, with an expansive alveolar surface area essential for gas exchange, equivalent to a tennis court (70-85 m2).
    • The conducting airways act as an anatomical dead space, meaning the first 150ml of each breath (or 30%) is used for passage before reaching the respiratory zone for gas exchange.

    Airways

    • The trachea connects the pharynx and larynx to the lungs, extending from the larynx (C6 vertebra) to the primary bronchi (T4/5 vertebral disc, varying from T4 to T6 depending on ventilation).
    • The trachea is a 2.5cm diameter tube, 10-15cm long, composed of 15-20 hyaline cartilaginous C-shaped rings and a complete cricoid cartilage, connected by fibrous annular ligaments.
    • The gap in the incomplete tracheal rings is filled by the trachealis muscle, innervated by the vagus nerve, allowing for changes in the tracheal lumen, especially during swallowing.

    Work of Breathing

    • The muscles of inspiration utilize 14-18% of oxygenated blood during exercise, while quiet breathing consumes about 10%.
    • Mechanical ventilation requires less oxygen as the work is performed externally.

    Bronchopulmonary Segments

    • Each lung consists of 10 bronchopulmonary segments, potentially fused together, with planes of connective tissue separating them.
    • Segments are comprised of a segmental (tertiary) bronchus, pulmonary artery branch, bronchial artery, and pulmonary veins, making each segment a distinct anatomical and functional unit.

    Trachea Relations

    • The aorta and major vessels lie anterior and left of the trachea, with the oesophagus positioned posteriorly.
    • The left recurrent laryngeal nerve runs between the oesophagus and trachea.
    • On the right, the right vagus nerve and azygos vein are in direct contact with the trachea, while on the left, the aortic arch and its branches separate the left vagus nerve from the trachea.

    Trachea Supply

    • The trachea receives blood supply from inferior thyroid and bronchial arteries.
    • Venous drainage occurs through the left brachiocephalic vein.
    • Lymphatic drainage occurs into pretracheal and paratracheal lymph nodes.
    • Sensory nerve supply comes from the vagi and recurrent laryngeal nerves.
    • Parasympathetic nerves innervate the trachealis muscle.

    Trachea Division

    • The trachea branches into two main bronchi at the concavity of the aorta.
    • The right main bronchus is shorter, wider, and more vertical than the left bronchus.

    Lobes of the Lung

    • Typically, the right lung has three lobes and the left has two, although fissure incompleteness or absence is possible.

    Borders of the Lung

    • Anterior: Thin, sharp, with a cardiac notch on the left exposing the pericardium (useful for pericardiocentesis).
    • Posterior: Rounded.
    • Inferior: Skirts around the lung base, thin and sharp at the costal surface, rounded at the mediastinal surface.

    Surfaces of the Lung

    • Costal: Smooth with rib furrows.
    • Mediastinal: Contains the lung hilum.
    • Diaphragmatic: Smooth, dome-shaped.

    Mediastinal Surface

    • Below the apex: Tracheal area anteriorly, oesophageal surface posteriorly.
    • Over the lung hilum: Groove for the azygos vein on the right, groove for the aortic arch on the left.

    Hila of the Lungs

    • Left hilum arrangement: Arteries Above, Bronchus at the Back, Veins in front (superior pulmonary vein) and below (inferior pulmonary vein).

    Hila of the Lungs

    • The lungs have a dual blood supply:
      • Deoxygenated blood from pulmonary arteries.
      • Oxygenated blood from bronchial arteries (two on the left, one on the right), branches of the descending aorta, following the bronchi.

    Bronchial Arteries

    • Most bronchial blood drains into the pulmonary veins, with some draining into the azygos and hemiazygos veins, creating a shunt in the circulation.

    Pleura Functions

    • Creates a moist, slippery surface for movement of the lungs within the thorax.
    • Maintains lung inflation even at rest, sticking the lungs to the thoracic cavity.

    Pulmonary Artery

    • The pulmonary trunk branches into left and right pulmonary arteries, with the right artery longer than the left, positioned horizontally between the superior vena cava and the right bronchus.
    • The right upper lobe bronchus artery runs anterior to the bronchus, while the right lower lobe bronchus artery arches over the bronchus intermedius (dividing into RLL and RML bronchi).

    Overview of the GIT Function

    • The gastrointestinal tract (GIT) is responsible for ingestion, chewing, propulsion, secretion of digestive juices and hormones, digestion, absorption, excretion, and defense against pathogens.

    • Sphincters control the flow of material through the GIT. There are two types:

      • Smooth muscle sphincters: Lower esophageal sphincter, pyloric sphincter, ileocecal sphincter, and internal anal sphincter.
      • Striated muscle sphincters: External anal sphincter (voluntary) and upper esophageal sphincter (involuntary).

    • The intestinal wall has several layers: Serosa, longitudinal smooth muscle, circular smooth muscle, submucosa, and mucosa.

    • Gastrointestinal smooth muscle functions as a syncytium, where gap junctions allow low-resistance movement of ions between muscle cells.

    • Muscle contraction types

      • Sphincters: Normally contracted, but occasionally relax completely.
      • Blood vessels and airways: Normally partially contracted with slight changes in contraction (tone).
      • Stomach and intestines: Phasically active with fluctuations in relaxation.
      • Oesophagus and urinary bladder: Normally relaxed but occasionally contract completely.

    • There are two types of muscle fiber activity:

      • Slow waves: Not action potentials, but slow undulating changes in resting membrane potential.
      • Spike potentials: True action potentials that occur automatically when the slow waves become more positive than -40 mV.

    Chewing and Swallowing

    • The chewing reflex is initiated by the presence of food in the mouth, leading to a sequence of muscle contractions and relaxations.

    • The tongue is composed mainly of skeletal muscle and plays a crucial role in positioning food for grinding.

    • The tongue's function in mastications relates to the progression of food, excoriation of the GIT, enzymatic action, and the rate of digestion.

    • Chewing is a voluntary motor activity controlled by the motor cortical areas and brainstem reticular areas through the motor component of the trigeminal nerve.

    • Xerostomia (dry mouth) is associated with a change in the composition of saliva or reduced salivary flow (hyposalivation).

    • Hyposalivation is often a side effect of medications, more common in older people, those who breathe through their mouths, in dehydration, and during radiotherapy involving salivary glands.

    • Saliva is secreted by three pairs of extrinsic salivary glands and small intrinsic buccal glands.

    • Saliva has many functions including:

      • Cleaning the mouth
      • Lubricating and protecting the oral cavity
      • Dissolving food chemicals
      • Moistening and compacting food

    • Saliva contributes to oral health by:

      • Washing away pathogens
      • Containing antimicrobial factors like thiocyanate ions, lysozyme, and antibodies.

    Salivary Secretion

    • Saliva contains high concentrations of potassium and bicarbonate with low concentrations of sodium and chloride compared to plasma.

    • The acini of salivary glands secrete a primary secretion containing ptyalin and mucin, undergoing compositional changes as it flows through the ducts.

    • Salivary secretion is primarily regulated by parasympathetic signals from the superior and inferior salivatory nuclei, which are stimulated by taste and tactile stimuli in the mouth and pharynx.

    • Salivation is also influenced by higher centers in the CNS including the appetite area, which is located near the parasympathetic centers of the anterior hypothalamus, responding to signals from the taste and smell areas of the cerebral cortex or amygdala.

    Salivation

    • Stimulated mainly by the parasympathetic division (VII, IX nerves)
    • Also triggered by sight, smell, thoughts of food and irritations in the lower GI tract
    • Kallikrein-bradykinin factors stimulate salivation
    • Sympathetic division and dehydration inhibit salivation
    • Average output of 1000-1500 ml/day

    Mucus

    • Provided by goblet cells along the entire GIT
    • Thick secretion composed mainly of water, electrolytes and glycoproteins
    • Features: lubrication, protection, adherent, coating, slippage, resistant to digestion, amphoteric properties and trapping network

    Oral Cavity

    • Well-vascularised
    • Drugs absorbed through the oral mucosa enter directly into the systemic circulation
    • Supplied by: maxillary, sphenopalatine, greater palatine, sublingual branch of the lingual artery

    Swallowing

    • Damage to CN V, CN IX and CN X can cause paralysis of the swallowing mechanism
    • Poliomyelitis or encephalitis can prevent normal swallowing by damaging the swallowing centre of the brain stem
    • Paralysis of the swallowing muscles (muscle dystrophy, myasthenia gravis, botulism) can also prevent normal swallowing
    • Under deep anaesthesia, patients my vomit large quantities of materials into the pharynx, then suck them into the trachea due to the anaesthetic blocking the reflex mechanism of swallowing
    • 40% of deaths due to stroke are attributable to defects in the swallowing mechanism

    Aspiration Pneumonia

    • Bronchopneumonia that develops due to the entrance of foreign materials into the bronchial tree (usually oral or gastric contents)
    • Chemical pneumonitis can develop, and bacterial pathogens may add to the inflammation
    • Iatrogenic cause is during general anaesthesia
    • Incompetent swallowing mechanism is the usual cause (neurological disease/injury, including multiple sclerosis, Alzheimer’s disease or intoxication)
    • Patients are instructed to be NPO (nothing by mouth) for at least 4 hours prior to surgery

    Nervous Control

    • Food bolus stimulates receptors in the pharynx
    • Impulses travel along sensory fibres of trigeminal and glossopharyngeal nerves
    • Signals are integrated in the swallowing centre (nucleus of the solitary tract, reticular substance of the bulb)
    • This causes:
      • Inhibition of respiratory centre in the medulla oblongata and pons, thus interruption of breathing to allow swallowing
      • Activation of the swallowing reflex (V, IX, X, XII)

    The Swallowing Act

    • Tongue thrust up and back
    • Nasopharynx closed
    • Larynx elevated
    • Airway closed
    • UES opened
    • Pharynx contracted
    • More than 20 muscles are involved

    Upper Oesophageal Sphincter (UES)

    • Made up of striated muscle
    • Not under voluntary control
    • Relaxed (opens) by swallowing

    Oesophagus

    • Muscular 25cm tube
    • Collapsed when not involved in food propulsion
    • Secretions: mainly mucous in character for lubrication

    Oesophageal Glands

    • Simple glands line the main body of the oesophagus
    • Compound glands are present in the:
      • Upper oesophagus preventing mucosal excoriation by newly entering food
      • Oesophago-gastric junction protecting the oesophageal wall from digestion by acidic gastric juices

    Oesophageal Musculature

    • Striated muscle in the pharyngeal wall and the upper third of the oesophagus
    • Smooth muscle in the lower two thirds of the oesophagus

    Oesophageal Peristalsis

    • Primary peristalsis: continuation of the peristaltic wave from the pharynx
    • Secondary peristalsis: caused by distention of the oesophagus sensed by stretch receptors

    Lower Oesophageal Tract

    • Smooth muscle controlled by the dorsal motor nucleus of the vagus nerve
    • A functional sphincter (not anatomical)
    • Histology distinct from the stomach
    • Can become dysfunction in:
      • Achalasia
      • GERD
      • Parkinson’s

    Investigative Techniques

    • Fluoroscopy: imaging technique using X-rays to obtain real-time moving images of the interior of an object
    • Manometry: test to measure the function of the oesophagus

    Gastroesophageal Reflux Disease (GERD)

    • Digestive disorder that affects the LES
    • Causes:
      • Heartburn
      • Chest pain
      • Acid indigestion

    Hiatal Hernia

    • Stomach bulges up into the chest through the hiatus
    • Types: Sliding or paraesophageal

    Swallow Syncope

    • Temporary loss of consciousness caused by a fall in blood pressure when swallowing

    Achalasia

    • Failure of smooth muscle fibres to relax, causing the LES to remain closed
    • Marked reduction of NO and VIP-containing neurons in the myenteric plexus of the lower oesophagus and LES
    • Results in:
      • Stasis of food
      • Putrid infection
      • Mucosal ulcerations
      • Substernal pain
      • Megaoesophagus (dilation of oesophagus) with possible rupture and death

    Heartburn

    • Burning sensation in the chest which may radiate to the neck, throat or angle of the jaw
    • In pregnancy, progesterone inhibits gastric motility and causes smooth muscles relaxation in the uterus and LES, causing gastroesophageal reflux that results in heartburn

    Stomach Functions

    • Storage
    • Chyme formation
    • Gastric juice secretion
    • Digestion and absorption of alcohol/caffeine/aspirin/etc.

    Vagovagal Reflex

    • When the stomach is distended, the stomach stretch-receptors send impulses via vagal afferent nerves to the CNS
    • CNS sends back vagal efferent impulses to the enteric nervous system
    • This activates inhibitory motor neurons and causes stomach muscle relaxation

    Stomach Relaxation

    • A bolus in the pharynx and oesophagus causes the vagovagal reflex in the oesophagus, resulting in:
      • Activation of inhibitory motor neurons releasing VIP
      • Receptive relaxation of the stomach
    • This decreases gastric pressure to allow the bolus to enter the stomach where it activates the vagovagal reflex, causing:
      • Adaptive relaxation of the stomach

    Gastric Relaxation Reflex

    • Malfunction results in:
      • Reflux
      • Weight loss
      • Early satiety

    Slow Waves

    • Propagate as a band toward the pylorus, activating contractions as smooth muscle cells depolarise, from the fundus to the corpus to the antrum and finally the terminal antrum
    • Dominant pacemaker produces 3 cycles per minute while the antral pacemaker produces 1 cycle per minute
    • Entire stomach frequency runs at the frequency of the dominant (corpus) pacemaker

    Stomach Emptying

    • Intense contractions, beginning in mid-stomach and spreading through the caudad stomach
    • Strong peristaltic, very tight ring-like constrictions
    • As the stomach becomes progressively emptier, the constrictions begin farther and farther up the body of the stomach
    • Not dependent on increased pressure
    • Stretching of the wall triggers local myenteric refluxes which accentuate the pyloric pump

    Chyme Emerging From The Stomach

    • pH approximately 2

    Gut-Associated Lymphoid Tissue (GALT)

    • GI tract’s immune system
    • Largest mass of lymphoid tissue in the human body

    Enterogastric Reflex

    • Activated by factors in the duodenum
      • Stretching of duodenal wall
      • Irritation of duodenal mucosa
      • Acidic chyme/protein/fat in the duodenum
      • Hypertonic/hypotonic chyme in the duodenum
    • These factors inhibit the stomach’s contents from emptying into the small intestine
    • Reflexes are sent from the duodenum to the stomach to slow/stop stomach emptying if the volume of the chyme is too much
    • Mediated by three routs:
      • Enteric nervous system in gut wall
      • Prevertebral sympathetic ganglia
      • Vagus nerve
    • All three routes strongly inhibit the pyloric pump propulsive contractions and increase the tone of the pyloric sphincter, resulting in a decrease in stomach emptying
    • Especially sensitive to presence of irritants and acids in the duodenum

    Hormones And Stomach Emptying

    • CCK, secretin and GIP are all released from the upper intestine in response to fats and inhibit stomach emptying

    Gastroparesis

    • Delayed gastric emptying
    • Partial paralysis of stomach
    • Can be caused by vagus nerve damage
    • Transient gastroparesis may arise as a consequence of:
      • Type 1 or type 2 diabetes
      • Anorexia nervosa
      • Bulimia nervosa
      • Parkinson's disease
      • Mitochondrial disease
      • Abnormal surgery
      • Heavy cigarette smoking

    Nasogastric Tube Placement

    • For:
      • Enteral feeding
      • Medication administration
      • Gastric decompression
      • To allow continuous aspiration of retained gastric contents

    Gastric Secretion

    Oxyntic Glands (Gastric Glands)

    • Secrete:
      • HCl
      • Pepsinogen
      • Intrinsic factor
      • Mucus
    • Found in the body and fundus of the stomach (80%)
    • Contains three main cell types:
      • Mucous neck cells: Mucus
      • Peptic/chief cells: Pepsinogen
      • Parietal/oxyntic cells: HCl and intrinsic factor

    Pyloric Glands

    • Mainly secrete mucus, but also secrete gastrin
    • Located in the antrum of the pylorus (the distal 20% of the stomach)
    • They are branched, coiled, tubular glands that open into the deep gastric pits
    • Lack chief and parietal cells

    Surface Mucous Cells

    • Secrete large quantities of viscid mucus
    • Cover the entire surface of the stomach mucosa
    • Mucus secretion is affected by:
      • Aspirin
      • NSAIDs
      • PGE 2
      • Adrenalin
      • Stress
    • Mucus is alkaline

    Parietal Cells

    • Only cells that secrete HCl
    • Secretion is under continuous control by endocrine and nervous signals and by ECL cells

    Enterochromaffin-Like Cells (ECL Cells)

    • Primary function is to secrete histamine
    • Lie in the deep recesses of the oxyntic glands
    • Release histamine in direct contact with parietal cells
    • Rate of HCl production is directly related to histamine secretion
    • Stimulated to secrete histamine by:
      • Gastrin (formed in the antrum)
      • Hormones

    Gastrin

    • Hormone secreted by gastrin cells (G cells) in the pyloric glands in the antrum
    • Large polypeptide secreted in two forms:
      • G34
      • G17 (numbers indicate the number of amino acids)
    • Smaller form is more abundant
    • Some proteins stimulate G cells to secrete gastrin into the blood, to be transported to ECL cells, causing histamine release which stimulates HCl secretion

    Somatostatin

    • High acidity in the antrum stimulates somatostatin release by D cells to inhibit meal-stimulated gastrin secretion

    Vagus Nerve

    • Can stimulate Ach release to act directly and indirectly (by stimulating ECL cells) on parietal cells to release HCl
    • The vagus also acts on G cells via gastrin-releasing peptide) to stimulate gastrin release to stimulate further HCl release

    HCl Secretion By Parietal Cells

    • Parietal cells contain large branching intracellular canaliculi.
    • HCl is formed at the villus-like projections inside these canaliculi and is then conducted through the canaliculi to the secretory end of the cell
    • Main driving force for HCl secretion by the parietal cells is the H+-K+ ATPase

    HCl Formation

    • H+ enters from the parietal cell into the canaliculus lumen in exchange for K+, using ATP. K+ tends to leak back into the lumen.
    • At the basolateral end, Na+ is taken out from the parietal cell into the interstitial fluid in exchange for K+, resulting in low intracellular Na+. Therefore Na+ enters the parietal cell from the canaliculus lumen. Hence, most of the K+ and Na+ is reabsorbed into the cell cytoplasm and H+ take their place in the canaliculus.
    • Pumping of H+ out of the cell allows OH- to accumulate within the parietal cell and bind with CO2 to form HCO3- by carbonic anhydrase. This is then transported into the extracellular fluid in exchange for Cl-, which enter the cell.
    • These Cl- are secreted through chloride channels into the canaliculus, binding with H+ to form HCl. This is then secreted outward through the open end of the canaliculus into the lumen of the gland
    • Water passes into the canaliculus by osmosis due to the extra ions being secreted into the canaliculus. Hence, the final secretion contains water, HCl (150-160mEq/L), KCl (15mEq/L) and a small amount of NaCl.

    Hydrochloric Acid

    • Released at 150mM/L
    • pH of 0.8
    • Isotonic
    • 1500cal/L
    • Functions:
      • Conversion of pepsinogen to pepsin
      • Bactericidal
      • Fe3+ reduction to Fe2+
      • Secretion and somatostatin release stimulation
      • Chyme formation and protein denaturation

    Inter-Digestive Period

    • Stomach secretes a few millilitres of gastric juice each hour
    • Almost entirely of the non-oxyntic type
    • Mainly mucus with little pepsin and no acid

    Emotional Stimuli

    • May increase inter-digestive gastric secretion, contributing to stress ulcers

    Gastrin, CCK and Secretin

    • All large polypeptides
    • Terminal 5 amino acids in gastrin and CCK are the same

    Pentagastrin

    • Synthesis gastrin composed of the terminal four amino acids to natural gastric plus the amino acid alanine
    • Has all the same properties as the natural gastrin

    Chronic Gastritis

    • Stomach lining becomes inflamed
    • Can cause destruction of parietal cells, which results in:
      • Achlorhydria (lack of stomach acid secretion)
      • Pernicious anaemia (anaemia from lack of intrinsic factor) due to failure of maturation of RBCs in the absence of vitamin B12 stimulation of the bone marrow

    Pernicious Anaemia

    • Bacterial overgrowth and B12 deficiency

    Vitamin B12

    • Vitamin B12 deficiency can cause a range of symptoms such as visual changes, tingling sensations, balance problems, memory issues, hallucinations, limb weakness, gait disturbance, and personality/mood shifts.
    • Vitamin B12 (Cobalamin) is found in animal products like eggs, milk, cheese, meat, fish, shellfish, and poultry.
    • Some soy products are fortified with Vitamin B12.
    • Slight Vitamin B12 deficiency can lead to anemia, fatigue, mania, and depression.
    • Long-term deficiency can result in permanent brain and central nervous system damage.
    • Vitamin B12 is produced only by bacteria and found naturally only in animal products.
    • Large doses of Vitamin B12 can be consumed as excess is excreted or stored (stores last up to a year).

    Vitamin B12 Absorption

    • Vitamin B12 initially binds to haptocorrin in saliva forming a complex resistant to gastric juices.
    • In the proximal small intestine, pancreatic enzymes cleave the complex.
    • Vitamin B12 then binds to intrinsic factor forming another complex resistant to proteolysis and absorption in the proximal small intestine.
    • The complex is absorbed in the ileum by receptor-mediated endocytosis, utilizing cubilin.
    • Vitamin B12 is transported to the liver via the portal blood, where it is stored.
    • It can also travel in the blood bound to transcobalamin II.

    Helicobacter pylori

    • Helicobacter pylori infection can cause peptic ulcers.
    • It infects the antrum, causing inflammation (gastritis), often asymptomatic.
    • This leads to a duodenal or gastric ulcer, potentially causing bleeding or perforation.

    Pepsinogen

    • Pepsinogen is released without digestive activity.
    • Activated to pepsin by HCl, changing its molecular weight from 42,500 to 35,000.
    • Pepsin has no proteolytic activity above pH 5.

    Gastric Secretion Phases

    • Cephalic Phase: Before food enters the stomach. Sight, smell, thought, or taste initiate signals originating in the cerebral cortex and appetite centers of the amygdala and hypothalamus.
    • Signals are transmitted through the dorsal motor nuclei of vagi and then through vagus nerves to the stomach. This phase accounts for about 30% of gastric secretion.
    • Gastric Phase: Food stimulates long vagovagal reflexes, local enteric reflexes, and the gastrin mechanism. This phase accounts for approximately 60% of gastric secretion.
    • Intestinal Phase: The presence of food in the duodenum accounts for 10% of gastric secretion.

    Inhibition of Gastric Secretion

    • Intestinal chyme initially stimulates gastric secretion during the early intestinal phase but inhibits it subsequently.
    • Enterogastric Reflex: The presence of food in the small intestines initiates a reverse enterogastric reflex. This reflex is transmitted through the myenteric nervous system and extrinsic sympathetic and vagus nerves, inhibiting stomach secretion. The reflex is triggered by small bowel distension, the presence of acid or protein breakdown products, or irritation of the mucosa.
    • Hormones: Presence of acid, fat, protein degradation products, hyperosmotic or hypo-osmotic fluids, or any irritating factor in the upper small intestine causes the release of secretin, which opposes stomach secretion. They also trigger the secretion of P, vasoactive intestinal polypeptide, and somatostatin, all of which inhibit gastric secretion.

    Ghrelin

    • Ghrelin is a hormone predominantly secreted from the stomach into circulation.
    • It stimulates growth hormone release, appetite, and food intake.
    • Ghrelin is beneficial for treating weight loss and eating disorders.
    • It improves cardiovascular function.

    Ghrelin and Leptin

    • The arcuate nucleus of the hypothalamus is the main target for ghrelin and leptin (secreted by adipose tissue).
    • Ghrelin is orexigenic (appetite stimulant), while leptin is anorexigenic (suppressing appetite).
    • Ghrelin stimulates neurons in the nucleus expressing neuropeptide Y and agouti-related peptide, while leptin suppresses them.

    Neuropeptide Y

    • Neuropeptide Y is released in response to ghrelin, stimulating appetite and increasing body weight.

    Gastric Bypass

    • A procedure used to treat severe obesity.
    • Reduces the space in the gastric cavity for food, thereby reducing total caloric intake.
    • The mean plasma ghrelin concentration decreases significantly after gastric bypass.

    Pancreas (General)

    • Located parallel to and beneath the stomach.
    • A large compound gland.
    • Its internal structure is similar to that of the salivary glands.

    Pancreatic Secretion

    • Pancreatic digestive enzymes are secreted by pancreatic acini, while sodium bicarbonate solution is secreted by small ductules and larger ducts leading from the acini.
    • This combination of enzymes and sodium bicarbonate flows through a long pancreatic duct that usually joins the hepatic duct before emptying into the duodenum via the papilla of Vater, surrounded by the sphincter of Oddi.
    • Pancreatic juice secretion is most abundant in response to chyme presence in the upper small intestine.
    • The characteristics of pancreatic juice are influenced by the types of food found in the chyme.
    • The pancreas also secretes insulin, but not by the same pancreatic tissue that secretes intestinal pancreatic juice. Insulin is released directly into the blood by the islets of Langerhans.

    Sphincter of Oddi

    • A small but powerful muscle ring situated at the junction of the bile and pancreatic juice ducts.
    • Regulates the flow of both substances into the duodenum.
    • After meals, especially rich or fatty ones, the gallbladder contracts to release bile.
    • The sphincter of Oddi relaxes to facilitate bile flow into the duodenum.
    • Any muscle abnormality affecting its proper relaxation can cause bile and pancreatic secretions to accumulate and backflow, leading to stagnation.
    • This accumulation results in forceful contraction of the distended tube, causing severe cramping and right upper abdominal pain.
    • Odditis is inflammation of the sphincter of Oddi.

    Secretin

    • Acidification of the duodenal lumen is the most potent stimulus for secretin release from S cells.
    • Secretion begins when the pH drops below 4.5 and reaches its peak at pH 3.
    • Secretin promotes the secretion of aqueous NaHCO3 solution from ductal cells, raising pH.
    • Therefore, secretin acts as nature's antacid.
    • Protects the small intestinal mucosa from the digestive activity of acidic gastric juice, preventing duodenal ulcers.
    • HCl + NaHCO3 → NaCl + H2CO3
    • Carbonic acid (H2CO3) immediately dissociates into CO2 (absorbed into the blood and exhaled through the lungs) and water.

    Pancreatic Juice Composition

    • Pancreatic secretion contains multiple enzymes and a large quantity of bicarbonate ions for neutralization.
    • Pancreatic Amylase: Digests carbohydrates. It hydrolyzes starches, glycogen, and most carbohydrates (except cellulose), primarily into disaccharides and a few trisaccharides.
    • Pancreatic Lipase: Neutralizes fat into fatty acids and monoglycerides.
    • Cholesterol Esterase: Hydrolyzes cholesterol esters.
    • Phospholipase: Splits fatty acids from phospholipids.
    • Trypsin, Chymotrypsin, and Carboxypeptidase: Important pancreatic enzymes for protein digestion. Trypsin is the most abundant.
    • Trypsin and Chymotrypsin: Split whole proteins into peptides of various sizes.
    • Carboxypeptidase: Splits some peptides into individual amino acids.

    Pancreatic Enzyme Activation

    • All three protein-digesting enzymes are released as zymogens, becoming activated in the intestinal tract.
    • Trypsinogen is activated by enterokinase (secreted by the intestinal mucosa when chyme contacts it).
    • Activated trypsin can then activate more trypsinogen, as well as chymotrypsinogen and procarboxypolypeptidase.

    Trypsin Inhibitor

    • The same cells that secrete proteolytic enzymes into the acini also secrete trypsin inhibitor.
    • It is formed in the cytoplasm of the glandular cells and prevents trypsin activation within the secretory cells, as well as in the acini and ducts of the pancreas.
    • This prevents the pancreas from digesting itself.

    Acute Pancreatitis

    • When the pancreas is severely damaged or a duct is blocked, large amounts of pancreatic secretion may accumulate in the damaged areas.
    • The trypsin inhibitor's effect is often overwhelmed, and the pancreas digests itself within hours, causing acute pancreatitis.
    • This condition is sometimes lethal due to circulatory shock.
    • If not lethal, it is likely to lead to lifelong pancreatic insufficiency.

    Bicarbonate Secretion

    • While pancreatic enzymes are secreted solely by the acini of the pancreatic glands, bicarbonate ions and water are primarily secreted by the epithelial cells of the ductules and ducts leading from the acini.
    • Bicarbonate ion concentration can rise to 145 mEq/L (five times the plasma concentration), providing a large amount of alkali in the pancreatic juice essential for HCl neutralization.
    • Steps of Bicarbonate Secretion:
      • CO2 from the blood enters the cell. Carbonic anhydrase facilitates its combination with water, forming carbonic acid. This dissociates into bicarbonate and hydrogen ions.
      • Additional bicarbonate ions enter the cell through co-transport with sodium ions.
      • Bicarbonate ions are exchanged for Cl- at the luminal border via secondary active transport. The entering chloride is recycled back into the lumen through specialized chloride channels.
      • Hydrogen ions generated by the dissociation are exchanged for Na+ at the basolateral membrane. Na+ enters through co-transport with bicarbonate and is then transported across the luminal border into the lumen. The negatively charged lumen also draws Na+ through tight junctions between cells.
      • This overall movement creates an osmotic pressure gradient, causing water to also move into the pancreatic duct.

    Secretin and Bicarbonate Secretion

    • Secretin directly stimulates epithelial cells to secrete bicarbonate ions into the ductal lumen, followed by water to maintain osmotic equilibrium.
    • Secretin increases cAMP in ductal cells, thereby opening CFTR Cl- channels to exchange Cl- for bicarbonate.
    • This indicates that the bicarbonate secretory process is dependent on CFTR, explaining why pancreatic dysfunction is seen in cystic fibrosis (CFTR mutation).

    Thymosin-alpha1

    • Thymosin-alpha1 is a potential therapy for cystic fibrosis, as it promotes increased residual activity of mutant CFTR channels and facilitates proper trafficking of mutant CFTR to the plasma membrane.

    Brunner's Glands

    • A vast array of compound mucous glands positioned in the wall of the initial centimeters of the duodenum, primarily between the pylorus and papilla of Vater.
    • Secrete significant quantities of alkaline mucus in response to tactile or irritating stimuli on the duodenal mucosa, vagal stimulation, and GI hormones (particularly secretin).

    Brunner's Gland Function

    • The alkaline mucus protects the duodenal wall from digestion by highly acidic gastric juice and neutralizes HCl.
    • Brunner's glands also secrete urogastrone, which inhibits parietal and chief cells in the stomach from secreting acid and digestive juices.
    • Brunner's glands are inhibited by sympathetic stimulation. Therefore, sympathetic stimulation in highly excitable individuals may leave this area of the duodenum unprotected, making it prone to developing peptic ulcers (in 50% of ulcer patients).

    Cholecystokinin (CCK)

    • The product of I cells, located in the small intestinal epithelium.
    • They release CCK into the interstitial space in response to free fatty acids and specific amino acids in the lumen.
    • CCK release is also regulated by CCK-releasing factor (secreted by paracrine cells within the epithelium) and monitor peptide (released by pancreatic acinar cells).
    • These hormones are also released in response to neural input, particularly important in the cephalic and gastric phases.

    CCK Functions

    • CCK causes the secretion of more pancreatic digestive enzymes from the acinar cells. This occurs through two mechanisms:
      • CCK acts as a classical hormone, traveling through the bloodstream to interact with acinar cell CCK1 receptors.
      • It stimulates neural reflex pathways that affect the pancreas. Vagal afferent nerve endings respond to CCK, activating a vagovagal reflex that enhances acinar cell secretion by activating pancreatic enteric neurons and releasing neurotransmitters such as acetylcholine, gastrin-releasing peptide, and VIP.

    Pancreatic Secretion Phases

    • Cephalic Phase: The same nervous signals from the brain that initiate gastric secretion also cause ACh release from vagal nerve endings in the pancreas. This triggers moderate enzyme secretion into pancreatic acini, accounting for about 20% of total pancreatic enzyme secretion. However, little of this secretion immediately flows through the pancreatic ducts into the intestine.
    • Gastric Phase: Nervous stimulation continues, accounting for 5-10% of pancreatic enzyme release. However, only small amounts reach the duodenum due to continued lack of significant fluid secretion.
    • Intestinal Phase: After chyme leaves the stomach, abundant pancreatic secretion occurs, mainly in response to secretin.

    Stimuli for Pancreatic Secretion

    • Three primary stimuli trigger pancreatic secretion:

      • Acetylcholine (ACh): Released from parasympathetic vagus nerve endings and other cholinergic nerves in the enteric nervous system.
      • Cholecystokinin (CCK): Secreted by duodenal and upper jejunal mucosa when food enters the small intestine.
      • Secretin: Secreted by the duodenal and jejunal mucosa when highly acidic food enters the small intestine.

    • ACh and CCK stimulate the acinar cells of the pancreas, causing the production of large quantities of digestive enzymes but relatively small amounts of water and electrolytes. Secretin then stimulates the release of abundant water solution of sodium bicarbonate, washing the enzymes into the duodenum.

    Secretin Function

    • Present in an inactive form (prosecretin) in S cells in the duodenal and jejunal mucosa.
    • When acidic chyme with a pH less than 5 enters the duodenum, it triggers release and activation of secretin, which is absorbed into the blood.
    • This stimulates the pancreas to secrete large quantities of fluid containing a high concentration of bicarbonate and a low concentration of chloride.
    • This mechanism is crucial for preventing ulcer formation.

    Bile Secretion

    • Daily bile production ranges from 600 to 1000 ml.
    • Plays a crucial role in fat digestion and absorption, as bile acids emulsify large fat particles into smaller ones, increasing their surface area for enzyme action.
    • Bile also aids in fat absorption through the intestinal mucosal membrane.
    • Additionally, bile serves as a means to excrete several important waste products from the blood, notably bilirubin and cholesterol.

    Bile Secretion Stages

    • The liver secretes bile in two stages:
      • Hepatocyte Secretion: The initial portion is secreted by hepatocytes. It contains significant amounts of bile acids, cholesterol, and other organic constituents. It is secreted into minute bile canaliculi situated between hepatic cells.
      • Secretion Through Bile Ducts: Bile then flows through these canaliculi towards the interlobular septa, where the canaliculi empty into terminal bile ducts. These join larger ducts, eventually reaching the hepatic duct and common bile duct. From here, bile either flows directly into the duodenum or is diverted through the cystic duct into the gallbladder.

    Bile Duct Secretion

    • As bile passes through the bile ducts, a water solution of sodium and bicarbonate ions secreted by epithelial cells is added to the initial bile.
    • This increases the total bile quantity by as much as 100%.
    • This secretion is stimulated especially by secretin for neutralization.

    Bile Storage and Emptying

    • The liver secretes bile, but it is stored by the gallbladder.
    • Gallbladder absorption occurs through the active transport of sodium, followed by secondary absorption of Cl-, H2O, and most other diffusible constituents.
    • When food is present in the upper gastrointestinal tract (GI) and especially when fatty foods reach the duodenum (approximately 30 minutes after a meal), the gallbladder begins to empty.
    • This emptying is achieved through rhythmic contractions of the gallbladder wall and simultaneous relaxation of the sphincter of Oddi, which controls the exit of the common bile duct.

    Gallbladder Emptying Stimuli

    • CCK is the most powerful stimulus for gallbladder contraction.
    • It is also moderately stimulated by ACh-secreting nerve fibers from both the vagi and the intestinal enteric nervous system.

    Bile Salt Synthesis

    • The precursor of bile salts is cholesterol, either from the diet or synthesized by the liver during fat metabolism.
    • Cholesterol is first converted into cholic acid or chenodeoxycholic acid.
    • These combine with glycine or taurine to form bile acids.
    • The salts of these acids are then secreted in the bile.

    Bile Salt Functions

    • Detergent/Emulsifying Action: Bile salts decrease surface tension, allowing for agitation of fats.
    • Absorption: Bile salts form small physical complexes called micelles, aiding in absorption.

    Liver Function

    • Filtration and Storage of Blood: The liver filters and stores blood.
    • Metabolism: It metabolizes carbohydrates, proteins, fats, hormones, and foreign chemicals.
    • Bile Formation: The liver produces bile.
    • Storage of Vitamins and Iron: The liver stores vitamins and iron.
    • Coagulation Factor Formation: The liver forms coagulation factors.

    Liver Anatomy

    • The largest organ in the body.
    • Hepatic Lobule: The basic functional unit of the liver. It contains a central vein, which empties into the hepatic veins and then the vena cava.
    • Cellular Plates: The lobule, composed of cellular plates, radiates from the central vein. Each plate is usually two cells thick,. Bile canaliculi situated between adjacent cells empty into bile ducts.
    • Portal Venules: Small portal venules are present in the septa. They receive blood mainly from the venous outflow of the GI tract through the portal vein. Blood from these venules flows into hepatic sinusoids located between the hepatic plates and then into the central vein.
    • Hepatic Arterioles: Hepatic arterioles are also present in the interlobular septa. They supply arterial blood to the septal tissues and often empty directly into the hepatic sinusoids.

    Liver Function

    • Liver Sinusoids: Lined by endothelial cells and Kupffer cells, which are resident macrophages that phagocytize bacteria and foreign matter from the hepatic sinus blood.
    • Spaces of Disse: Narrow tissue spaces between endothelial cells and hepatic cells that connect with lymph vessels.
    • Cirrhosis: Destruction of liver parenchymal cells and replacement by fibrous tissue, impeding portal blood flow. Caused by chronic alcoholism, excessive fat accumulation (non-alcoholic steatohepatitis), poisons, viral diseases, bile duct obstruction, and infections.
    • Non-alcoholic Fatty Liver Disease: Less severe form of fat accumulation and liver inflammation. Associated with obesity and type II diabetes.
    • Portal Hypertension: Caused by blockage of the portal vein or its branches, impeding blood flow and leading to increased capillary pressure in the intestinal wall. Can result in fluid loss from capillaries into the intestines, potentially leading to death.
    • Liver as Blood Reservoir: Liver can store up to 30% of the body's blood volume in cases of high right atrial pressure, especially during cardiac failure with peripheral congestion.
    • High Hepatic Vascular Pressures: Can cause fluid transudation into the abdominal cavity, leading to ascites.
    • Blockage of Portal Flow: Causes high capillary pressure in the portal vascular system of the gastrointestinal tract, resulting in gut wall edema and ascites.
    • Generalized Cellular Deterioration in Shock: Liver is particularly affected due to insufficient nutrients and exposure to vascular toxins.
    • Liver Regeneration: Possible after partial hepatectomy or acute liver injury, with hepatocytes replicating until the original size is restored.
    • Hepatocyte Growth Factor (HGF): Important in liver cell division and growth. Produced by mesenchymal cells, but not by hepatocytes. Levels increase significantly after hepatectomy. Other growth factors and cytokines may also play a role.
    • Transforming Growth Factor-beta (TGF-beta): Inhibits liver cell proliferation and may be the main terminator of liver regeneration.
    • Hepatic Macrophage System: Kupffer cells line hepatic venous sinuses to phagocytize bacteria from the gut.
    • Carbohydrate Metabolism in the Liver: Storage of glycogen, conversion of galactose and fructose to glucose, gluconeogenesis, and formation of chemical compounds from carbohydrate intermediates.
    • Fat Metabolism in the Liver: Oxidation of fatty acids, synthesis of cholesterol, phospholipids, and lipoproteins, and synthesis of fat from proteins and carbohydrates.
    • Beta-oxidation: Process of splitting fatty acids into two-carbon acetyl radicals that form acetyl CoA, which enters the citric acid cycle for energy production.
    • Cholesterol Synthesis: 80% of synthesized cholesterol is converted to bile salts, the remainder transported in lipoproteins to body cells.
    • Protein Metabolism in the Liver: Deamination of amino acids, formation of urea, synthesis of plasma proteins, interconversion of amino acids, and synthesis of other compounds.
    • Deamination of Amino Acids: Required for amino acid use in energy production or conversion to carbohydrates and fats.
    • Urea Formation: Removes ammonia from body fluids. High plasma ammonia levels can lead to hepatic coma.
    • Plasma Protein Synthesis: Hepatic cells produce all plasma proteins except gamma globulins (antibodies formed by plasma cells).
    • Liver as Vitamin Storage: Stores vitamins A, D, and B12.
    • Iron Storage: Liver stores ferritin, which releases iron when body fluids have low iron levels.
    • Coagulation Factors: Liver synthesizes fibrinogen, prothrombin, accelerator globulin, factor VII, and other clotting factors. Vitamin K is required for most of these.
    • Detoxification and Excretion: Liver detoxifies and excretes drugs, hormones, and calcium into bile.
    • Bilirubin Metabolism: Major end product of hemoglobin degradation, excreted in bile.
    • Hemoglobin Breakdown: Hemoglobin is broken down into globin and heme. Heme is then converted to biliverdin, and then to unconjugated bilirubin.
    • Conjugated Bilirubin: Unconjugated bilirubin is transported to the liver and conjugated with glucuronic acid or other substances, forming bilirubin glucuronide.
    • Bilirubin Excretion: Conjugated bilirubin is actively excreted from the hepatocytes into the bile canaliculi and then the intestines.
    • Urobilinogen Formation: In the intestines, some bilirubin is converted to urobilinogen, which is highly soluble.
    • Urobilinogen in Urine and Feces: Some urobilinogen is reabsorbed into the blood but most is re-excreted by the liver back into the gut. A small amount is excreted by the kidneys into the urine.
    • Jaundice: Yellowish tint of body tissues due to high bilirubin levels in extracellular fluids.
    • Causes of Jaundice: Increased RBC destruction (hemolytic jaundice), bile duct obstruction (obstructive jaundice), or liver cell damage.
    • Hemolytic Jaundice: Unconjugated bilirubin levels in the blood rise.
    • Obstructive Jaundice: Obstruction of bile ducts or damage to hepatic cells. Conjugated bilirubin levels in the blood rise.

    Digestion

    • Hydrolysis: Process of breaking down molecules by adding water.

    • Carbohydrate Digestion: Starch is hydrolyzed into maltose and smaller glucose polymers by salivary and pancreatic amylase.

    • Disaccharide Digestion: Enterocytes break down disaccharides into monosaccharides by enzymes like lactase, sucrase, maltase, and alpha-dextranase.

    • Protein Digestion: Pepsin, in the stomach, breaks down proteins into polypeptides.

    • Pancreatic Proteolytic Enzymes: Trypsin, chymotrypsin, carboxy-polypeptidase, and elastase further digest polypeptides into smaller peptides.

    • Enterocyte Peptidases: Split the remaining polypeptides into tripeptides, dipeptides, and amino acids.

    • Fat Digestion: Lipases in saliva and the pancreas break down triglycerides into free fatty acids.

    • Bile Salts: Emulsify fat globules and aid in transporting monoglycerides and free fatty acids to enterocytes.

    • Cholesterol Ester Hydrolase and Phospholipase A2: Hydrolyze cholesterol esters and phospholipids, releasing fatty acids.

    • Valvulae Conniventes (Folds of Kerckring): Circular folds in the small intestine that increase surface area.

    • Villi: Finger-like projections on the epithelial surface of the small intestine, further increasing surface area.

    • Microvilli: Tiny projections on the surface of enterocytes, again increasing surface area.

    • Pinocytic Vesicles: Invaginations of the enterocyte membrane forming vesicles that transport absorbed fluids.

    • Actin Filaments: Help with rhythmic contractions of the microvilli.

    • Water Transport: Occurs by osmosis, both paracellularly and transcellularly. Direction of transport depends on ingested food osmolarity.

    • Cholera Toxin: Produces cAMP, leading to increased secretion of water, sodium, potassium, and bicarbonate into the small intestine. Causes dehydration and diarrhea.

    • Hyponatraemia: Low sodium levels in the blood.

    • Cerebral Oedema: Severe hyponatraemia can cause brain swelling.

    • Aldosterone: Hormone that increases sodium absorption in the intestines.

    • Bicarbonate Secretion and Reabsorption: Pancreas secretes bicarbonate into the small intestine. Bicarbonate is reabsorbed in exchange for chloride.

    • Calcium Absorption: Primarily occurs in the duodenum, regulated by parathyroid hormone and vitamin D.

    • Iron Absorption: Actively absorbed from the small intestine.

    • Anaemia: Low red blood cell count, treated with oral iron supplementation.### Anaemia

    • Infants who do not receive enough iron in the diet are at risk of anaemia

    • Children during growth spurts are also at risk

    • Women who menstruate or have menstrual problems are at risk

    • Pregnant women are at risk

    • Individuals undergoing chemotherapy are at risk

    • People with haemorrhaging ulcers are at risk

    Absorption of Nutrients

    • Ascorbate and citrate increase iron uptake by acting as chelators to help solubilize iron
    • Potassium, magnesium and phosphate are actively absorbed
    • Monovalent ions are absorbed with ease and in high quantities
    • Bivalent ions are absorbed in small amounts
    • Glucose is absorbed in co-transport with sodium in two stages
      • Active transport of sodium ions through the basolateral membranes of the intestinal epithelial cells
      • Decrease in sodium inside the cells causes sodium from the intestinal lumen to move through the brush border of the epithelial cells to the interior by secondary active transport together with another substance such as glucose
    • Galactose is transported in the same way as glucose
    • Fructose is not absorbed by sodium co-transport
      • It is transported by facilitated diffusion
      • It is converted into glucose inside the cell and transported in the form of glucose into the blood
    • Peptides and amino acids are transported by co-transport with sodium
    • Micelles penetrate into the recesses among the microvilli
      • Monoglycerides and fatty acids diffuse out of the micelles and penetrate the interior of the epithelial cells
      • The bile micelles remain in the chyme
    • Fatty acids and monoglycerides are taken up by the cell's smooth ER where they form new triglycerides that are released in the form of chylomicrons to flow up through the thoracic lymph duct and empty into circulating blood
    • Small quantities of short- and medium-chain fatty acids are absorbed directly into the portal blood rather than being converted into triglycerides and absorbed by lymphatics
    • Most water and electrolytes left in the chyme after passing through the ileocaecal valve are absorbed by the colon
    • Most of this absorption occurs in the proximal half of the colon, giving this portion the name absorbing colon
    • The distal colon functions principally for faeces storage and is thus called storage colon

    Colon

    • The colon has a high capability for active absorption of sodium
    • The electrical potential gradient created causes chloride absorption
    • The tight junctions between the epithelial cells of the large intestinal epithelium are much tighter than those of the small intestine to prevent back-diffusion
    • The colon secretes bicarbonate ions while absorbing an equal number of chloride ions in exchange
      • This helps to neutralize the acidic end products of bacterial action
    • Cholera or certain bacterial infections can cause the crypts in the terminal ileum and large intestine to secrete fluids, leading to diarrhoea
    • The brown color of faeces is caused by stercobilin and urobilin

    Drug Metabolism

    • The pharmacokinetic process consists of
      • Absorption from the GI tract and other sites of administration into the blood
      • Distribution between the blood and sites of action
      • Metabolism between the blood and liver
      • Excretion from the kidneys
    • ADME determines how much of an administered dose gets to its sites of action
    • First pass effect: Phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation
    • Biotransformation: Chemical changes to a drug into a metabolite that can be easily eliminated from the body, by making it more water-soluble
      • The liver is primarily responsible for this task, but it can also occur in the plasma, kidneys, lungs and intestinal mucosa
    • Lipophilic drugs tend to be metabolised to a greater extent than hydrophilic drugs
    • DMEs (Drug metabolising enzymes)
      • Extrahepatic microsomal enzymes for oxidation and conjugation
      • Hepatic microsomal enzymes for oxidation and conjugation
      • Hepatic non-microsomal enzymes for acetylation, sulphation, GSH, alcohol/aldehyde dehydrogenase, hydrolysis, oxidation, reduction
    • DMEs are found in almost all organs, but especially the liver and the intestine
    • They are found in the cytosol, endoplasmic reticulum and mitochondrial inner plasma membrane in cells
    • CYP families: Cytochrome P450
      • Proteins of the superfamily containing heme as a cofactor
      • Most of DMEs are in CYP 1, 2 and 3 families
      • Frequently, two or more enzymes can catalyse the same type of oxidation
    • CYP3A4 is very common to the metabolism of many drugs
      • Its presence in the GI tract is responsible for poor oral availability of many drugs
    • Cytochromes vary in the structure of the heme and in its binding to apoprotein
    • Cytochromes of the c type contain a modified iron protoporphyrin IX known as heme c
    • Drugs usually undergo one or both of the following types of chemical reactions in the liver
      • Oxidation, hydrolysis or reduction to become more soluble
      • Conjugation, usually with glucose
    • Drugs that are administered orally normally travel first to the liver prior to entering the general circulation
      • This first-pass metabolism may cause significant deterioration (metabolism) of the active drug, thus rendering the drug inactive
    • Other non-microsomal reactions:
      • Hydrolysis in the plasma by esterases
      • Alcohol and aldehyde dehydrogenase in the cytosolic fraction of the liver
      • Monoamine oxidase in the mitochondria
      • Xanthene oxidase
      • Enzymes for particular drugs

    Factors that affect biotransformation

    • Age: Children have immature metabolising enzyme systems. Biotransformation is reduced in older persons
    • Sex: Women are more sensitive to ethanol
    • Clinical or physiological condition: Such as liver, cardiovascular or renal problems
    • Environmental factors: Smoking and alcohol
    • Genetics: Fast and slow metabolisers
    • Species differences
    • Induction and inhibition: Two major types of CYP inducers
      • Phenobarbital enhances metabolism of a wide variety of substrates by causing proliferation of SER and CYP in liver cells
      • Polycyclic aromatic hydrocarbons induce metabolism
      • Induction appears to be an environmental adaptive response of an organism
      • Orphan nuclear receptors are regulators of drug metabolising gene expression
    • Inhibitors prolong the action of drugs or inhibit the action of those biotransformed to active agents
    • Inducers shorten the action of drugs or increase the effects of those biotransformed to active agents
    • Blockers act on non-microsomal enzymes
    • Non-nitrogenous substances that affect drug metabolism include grapefruit juice, herbal products and isosafrole/safrole (found in root beer and perfume)
    • Grape juice elevates the plasma peak drug concentration but not the elimination half time
      • It reduces the metabolite to parent drug ‘area under the chart’ ratio
      • Effects last around 4 hours, thus requiring new enzyme synthesis
      • The effect is cumulative and highly variable amount individuals
    • Mutations can occur in genes, causing poor metabolisers, intermediate metabolisers and ultra-rapid metabolisers
    • Key receptors involved in metabolism are pregnane X receptor (PXR) and constitutive androstane receptor (CAR)
    • PXR: One of the nuclear receptor (NR) family of ligand-activated transcription factors
      • Named on basis of activation by pregnanes
      • Cloned due to homology with other nuclear receptors
      • Highly active in the liver and intestine
      • Binds as heterodimer with retinoic acid receptor (RXR)
    • CAR: Highly expressed in the liver and intestine
      • Sequestered in the cytoplasm
      • Co-factor complex required for activation
      • Anchored by PPAR-binding protein
      • Binds response elements as RXR heterodimer
      • High basal transcriptional activity without ligand
      • Activated by xenobiotics

    Gastrointestinal Motility

    • Parasympathetic stimulation causes increased peristalsis and relaxes sphincters
    • Sympathetic stimulation inhibits peristalsis and increases the tone of the sphincters
      • Net result of sympathetic stimulation is greatly slowed propulsion of food through the tract and sometimes decreased secretion
    • Peristalsis reflex: Complex pattern of contractions and relaxations of the GIT wall
      • Also called myenteric reflex since it does not occur in the absence of the myenteric plexus
    • Peristatic reflex plus the downstream direction of the movement of the peristalsis is called the law of the gut
    • Peristalsis: Propagating wave produced by simultaneous contraction of circular musculature and relaxation of longitudinal musculature and simultaneous relaxation of circular musculature and contraction of longitudinal muscular (downstream)
    • Physiological ileus: Condition characterised by the absence of motility in the small and large intestines
      • Functional condition programmed by the ENS and caused by the activity of inhibitory neurons that determines a temporary absence of motility
    • Paralytic ileus: Condition characterised by prolonged absence of motility
      • Caused by a state of uninterrupted activity of inhibitory neurons that prevents any motility
    • Auscultation for bowel sounds should hear 5-30 times/minute
    • Absence of peristalsis is characteristic of paralytic intestinal occlusion, linked to various conditions but especially to surgery
    • Motilin: Induces intense contractions that propagate caudally
    • Gastric motility in the fasted state is a cyclical phenomenon called the migrating motor complex
      • Phase 1: Quiescent period with virtually no contractions
      • Phase 2: Intermittent, irregular low-amplitude contractions
      • Phase 3: Short bursts of regular high-amplitude contractions. Periodically occur every 90-120 minutes in humans
      • Phase 4: Short transition period back to the quiescence of phase 1
    • Plasma motilin level is highly associated with the appearance of gastric phase 3 in humans
    • These are also called starvation contractions
    • In the stomach, the lower oesophageal sphincter contracts while the pylorus and ileocecal valve are completely open. Both the gastric and pancreatic secretions are stimulated
    • In the duodenum, peristaltic activity migrates through the duodenum, jejunum and ileum. The luminal GIT content is propelled caudally. Undigested food residues are cleared out and bacterial colonisation is reduced
    • Motilin: Induces intense contractions (phase 3) that propagate caudally. In humans, it is encoded by MLN gene. Secreted by endocrine M cells that are numerous in crypts of the small intestine (especially duodenum and jejunum). Released into the general circulation in humans about 100-minute intervals during the inter-digestive state.

    Ileocecal valve

    • Ileocecal valve protrudes into the lumen of the cecum and therefore is forcefully closed when excess pressure builds in the cecum and tries to push caecal contents backwards against the valve lips
    • Wall of the ileum for several centimetres immediately upstream from the ileocecal valve has a thickened circular muscle called the ileocecal sphincter that normally remains mildly constricted and slows emptying of ileal contents into the cecum
    • Ileocecal valve and sphincter prevent the passage of faecal matter back from the colon into the small intestine
    • The chyme stops at the level of the IC valve for several hours, prolonging the absorption of nutrients. The valve then opens when the subject ingests the next meal
    • The meal triggers the gastro-ileal reflex, which intensifies peristalsis in the ileum, opens the ileocecal valve and sphincter and promotes the passage of chyme into the colon
    • Gastrin, released from the gastric mucosa, stimulates peristalsis in the ileum and the relaxation of the IC valve
    • Gastro-ileal reflex is one of the three extrinsic reflexes of the GI tract. The other two are the gastrocolic reflex and the enterogastric reflex
    • The gastro-ileal reflex is stimulated by the presence of food in the stomach and by gastric peristalsis. Initiation of the reflex causes peristalsis in the ileum and the opening of the IC valve. This in turn stimulates colonic peristalsis and an urge to defecate
    • IC sphincter and peristalsis intensity are controlled significantly by reflexes from the cecum
    • Distension of the cecum causes contraction of the IC sphincter and ileal peristalsis inhibition, greatly delaying emptying of additional chyme into the cecum
    • Also, irritants in the cecum delay emptying, such as inflamed appendix, irritation of the vestigial remnant of the cecum and partial ileal paralysis block emptying into the cecum
    • Reflexes are mediated by the myenteric plexus and by extrinsic autonomic nerves, especially by way of the prevertebral sympathetic ganglia
    • IC valve dysfunction: Different symptoms are presented, which may include joint pain, sudden stabbing pain in the low back or leg, sharp/dull headaches, migraines, chronic sinus infection, allergies, dark circles under the eyes and general GI discomfort

    Large Intestine

    • Large intestine: cecum, ascending/transverse/descending colon, rectum and anus
    • Colon consists of functional layers with a columnar epithelium most closely opposed to the lumen, which then under-laid by the lamina propria, serosa and muscle layers
    • Colonic mucosa is surrounded by continuous layers of circular muscle that can occlude the lumen
      • Indeed, at intervals, the circular muscle contracts to divide the colon into segments called haustra
    • Primary functions of the large intestine are to digest and absorb what was not more proximally, reabsorb the remaining fluid and store the waste products
    • Commensal bacteria engage in a life-long symbiotic relationship with their human host. These bacteria can metabolise components of the meal and make the products available to the body via fermentation
      • Colonic bacteria also metabolise other endogenous materials

    Overview of the function of the GIT

    • The GIT is responsible for ingestion, chewing, propulsion, secretion, digestion, absorption, excretion and defense
    • Sphincters control the flow of food through the GIT
      • Smooth muscle: lower esophageal sphincter, pyloric, ileocecal, internal anal sphincter
      • Striated muscle: external anal sphincter (voluntary), upper esophageal sphincter (involuntary)
    • The GIT functions as a syncytium, allowing for the smooth movement of ions between muscle cells
    • The GIT experiences different types of contractions
      • Sphincters: normally contracted, occasionally relax completely
      • Blood vessels and airways: normally partially contracted, exhibit slight changes in tone, which is the normal level of firmness or slight contraction in a resting muscle
      • Stomach and intestines: experience fluctuations in relaxation, known as phasic activity
      • Oesophagus and urinary bladder: normally relaxed but occasionally experience complete contraction
    • The GIT experiences slow waves
      • Slow waves are not action potentials, but slow undulatory changes in the resting membrane potential
      • They do not usually cause muscle contractions by themselves, except in the stomach
      • Their frequency varies along the GIT, being 3 waves/min in the stomach body, 12 waves/min in the duodenum, and 9 waves/min in the terminal ileum
    • Interstitial cells of Cajal are pacemakers responsible for the bioelectrical slow waves
    • The GIT experiences spike potentials, which are triggered by slow waves
      • Spike potentials are true action potentials
      • The higher the slow wave potential rises, the greater the frequency of spike potentials
    • The GIT smooth muscle fibers allow entry of calcium and sodium ions, called calcium-sodium channels
    • These channels are slow to open and close, resulting in long-duration action potentials
    • The enteric nervous system controls GIT motility, secretion and blood flow
      • The enteric nervous system consists of the myenteric and submucosal plexuses
        • The myenteric plexus controls contractions
        • The submucosal plexus controls secretion and blood flow
    • Sensory information from the GIT is sent to the enteric nervous system and the CNS
    • Several neurotransmitters control GIT function, including acetylcholine, norepinephrine, serotonin, and dopamine
    • Acetylcholine excites GIT activity, while norepinephrine and epinephrine inhibit it
    • Parasympathetic innervation increases GIT activity, particularly in the upper part of the GIT
    • Sympathetic activation usually inhibits GIT function, except for sphincter contraction
    • Sensory innervation can cause excitation or inhibition depending on the conditions

    Chewing, Swallowing and Vomiting

    • The chewing reflex is stimulated by the presence of food in the mouth
    • The tongue is used to position food for grinding
    • Chewing plays a role in the progression of food, excoriation of the GIT, enzymatic action and rate of digestion
    • Xerostomia is dry mouth, associated with reduced salivary flow
    • Saliva is secreted by three pairs of extrinsic salivary glands and small intrinsic buccal glands
    • Saliva lubricates the oral cavity, dissolves food chemicals, moistens food, and prevents the deterioration of food
      • Saliva contains thiocyanate ions, proteolytic enzymes, lysozyme, and antibodies that kill bacteria
      • Saliva contains haptocorrin (aka TC-1/cobalophilin/R-protein/R-factor) which protects vitamin B12
    • Saliva contains large quantities of potassium and bicarbonate ions, and low concentrations of sodium and chloride ions compared to plasma
    • Parasympathetic nerves stimulate salivary gland secretion
      • Salivatory nuclei in the medulla and pons are responsible for salivary gland stimulation
    • The appetite area in the hypothalamus plays a role in regulating salivation

    Salivation

    • Salivation is stimulated primarily by the parasympathetic division (salivatory nuclei and VII, IX nerves)
    • Salivation is triggered by sight, smell, though of food and irritations in the lower GI tract
    • Salivation is stimulated by the kallikrein-bradykinin factors
    • Salivation is inhibited by the sympathetic division and dehydration
    • Average daily output of saliva: 1000-1500ml
    • Sympathetic stimulation can slightly increase salivation
    • Stomach and upper small intestines can initiate salivary reflexes in response to irritating foods or nausea.
    • Blood supply to salivary glands influences secretion as salivary glands require nutrients from the blood.

    Mucus

    • Mucus is provided by billions of single-cell mucous glands (aka goblet cells) present along the entire GIT
    • Thick secretion composed mainly of water, electrolytes and several glycoproteins (large polysaccharides bound with protein).
    • Mucus features include lubricant, protection, adherent, coating, slippage, resistant to digestion, and amphoteric properties.

    Oral Cavity

    • The oral cavity is well-vascularised, thus drugs absorbed through the oral mucosa enter directly into the systemic circulation, hence having a rapid onset of action.
    • Several cardiovascular drugs are administered transmucosally (e.g. nitro-glycerine)
    • Damage to CN V, CN IX and CN X can cause paralysis of the swallowing mechanism.
    • Poliomyelitis or encephalitis can prevent normal swallowing by damaging the swallowing centre of the brain stem.
    • Paralysis of the swallowing muscles, which occurs in muscle dystrophy, myasthenia gravis or botulism, can also prevent normal swallowing.

    Swallowing

    • Swallowing: Tongue thrusts up and back, nasopharynx is closed, larynx is elevated, airway is closed, UES opens, and the pharynx contracts.
    • More than 20 muscles are involved in the swallowing mechanism
    • Sensory fibres of the trigeminal and glossopharyngeal nerves carry impulses from the bolus to the swallowing centre.
    • The swallowing centre is located in the nucleus of the solitary tract and the reticular substance of the bulb.
    • The swallowing centre inhibits the respiratory centre in the medulla oblongata and pons to interrupt breathing during swallowing.
    • Swallowing activates the swallowing reflex (V, IX, X, XII)

    Aspiration Pneumonia

    • Bronchopneumonia that develops due to the entrance of foreign materials into the bronchial tree. (usually oral or gastric contents)
    • Iatrogenic cause: occurs during general anaesthesia; thus, patients are instructed to be nil per os (abbreviated as NPO) i.e. nothing by mouth for at least 4 hours prior to surgery.
    • Chemical pneumonitis can develop, and bacterial pathogens may add to the inflammation.
    • Cause is usually an incompetent swallowing mechanism, e.g. due to neurological disease/injury, including multiple sclerosis, Alzheimer’s disease or intoxication.

    Oesophagus Physiology

    • Oesophagus: Muscular 25cm tube.Collapsed when not involved in food propulsion.
    • Secretions: Simple and compound mucous glands.
    • Simple glands lining the oesophagus secrete entirely mucous in character, mainly for lubrication during swallowing.
    • Compound glands: in the upper oesophagus, they prevent mucosal excoriation by newly entering food. At the oesophago-gastric junction, they protect the oesophageal wall from digestion by acidic gastric juices that often reflux from the stomach back into the lower oesophagus.
    • Peptic ulcers can occur at the gastric end of the oesophagus
    • The musculature of the pharyngeal wall and the upper third of the oesophagus is striated muscle. Thus, peristaltic waves in these regions are controlled by skeletal nerve impulses from the glossopharyngeal and vagus nerves.
    • In the lower two thirds of the oesophagus, musculature is smooth muscle. However, this portion is strongly controlled by the vagus nerve via the oesophageal myenteric nervous system.
    • The oesophageal myenteric nervous system would still be able to cause strong secondary peristaltic waves without support from the vagal reflexes. Therefore, even after paralysis of the brain stem swallowing reflex, food fed by a tube or in some other way into the oesophagus readily passes into the stomach.

    Oesophageal Peristalsis

    • Primary peristalsis: Continuation of the peristaltic wave that begins in the pharynx and spreads into the oesophagus during the pharyngeal stage of swallowing. Lasts 8 to 10 seconds, and 5 to 8 seconds if the person is upright.
    • Secondary peristalsis: Caused by the distention of the oesophagus itself sensed by stretch receptors, occurring when the retained food if the primary peristaltic wave fails to move all the food. These waves are initiated partly by the myenteric plexus system and partly by reflexes beginning in the pharynx that are transmitted to the medulla by the vagus and back again to the oesophagus through the glossopharyngeal and vagus nerve.
    • Food can reach the stomach even if the person is upside down.

    Lower Oesophageal Tract

    • Smooth muscle controlled by the dorsal motor nucleus of the vagus nerve.
    • It is a functional sphincter (not anatomical) with histology distinct from the stomach.
    • Dysfunctions include: achalasia, GERD, Parkinson’s.
    • Fluoroscopy: Imaging technique using X-rays to obtain real-time moving images of the interior of an object. Contrast (usually barium sulfate with water) is swallowed, since it enhances the visibility of the relevant parts of the GI tract by coating the inside and appearing white on the film.

    Manometry

    • Test to measure the function of the oesophagus.
    • Thin, pressure-sensitive tube is passed through the down into the stomach. Numbing medicine inside the nose.
    • After the tube is in the stomach, it is pulled slowly back into the oesophagus and the patient is asked to swallow.
    • Pressure of muscle contractions is measured along several sections of the tube.
    • Other studies can be done while the tube is in place.
    • Takes about an hour.

    Gastroesophageal Reflux Disease

    • Digestive disorder that affects the LES.
    • Causes heartburn, chest pain or acid indigestion.

    Hiatal Hernia

    • Stomach bulges up into the chest through the hiatus.
    • Can be sliding or paraesophageal.

    Swallow Syncope

    • Temporary loss of consciousness caused by a fall in blood pressure when swallowing.

    Achalasia

    • Failure of smooth muscle fibres to relax, which can cause the lower oesophageal sphincter to remain closed.
    • Marked reduction of NO and VIP-containing neurons in the myenteric plexus of the lower oesophagus and LES cause them to remain contracted, resulting in stasis of food, putrid infection, mucosal ulcerations and substernal pain.
    • This might result in megaoesophagus (dilation of oesophagus) with possible rupture and death.

    Heartburn

    • Aka pyrosis, cardialgia or acid indigestion.
    • Burning sensation in the chest which may radiate to the neck, throat or angle of the jaw.
    • In pregnancy, the placenta secretes progesterone that inhibits gastric motility and causes smooth muscle relaxation in the uterus and LES, causing gastroesophageal reflux that results in heartburn.

    Stomach Functions:

    • Storage
    • Chyme formation
    • Gastric juice secretion
    • Digestion and absorption of alcohol/caffeine/aspirin/etc.

    Vagovagal Reflex

    • When the stomach is distended, the stomach stretch-receptors send impulses via vagal afferent nerves to the CNS, which sends back vagal efferent impulses to the enteric nervous system, activating inhibitory motor neurons and causing stomach muscle relaxation.

    Stomach Relaxation

    • A bolus in the pharynx and oesophagus causes the vagovagal reflex in the oesophagus which results in activation of inhibitory motor neurons releasing VIP which causes receptive relaxation of the stomach.
    • This decreases gastric pressure to allow the bolus to enter the stomach where it activates the vagovagal reflex, causing adaptive relaxation of the stomach.

    Malfunction of Gastric Relaxation Reflexes

    • Result in reflux, weight loss and early satiety.

    Stomach Contractions

    • Slow waves propagate as a band toward the pylorus, activating contractions as smooth muscle cells depolarise, from the fundus to the corpus to the antrum and finally the terminal antrum.
    • Dominant pacemaker produces 3 cycles per minute while the antral pacemaker produces 1 cycle per minute.
    • The frequency of the entire stomach runs at the frequency of the dominant (corpus) pacemaker.

    Stomach Emptying

    • Intense contractions, beginning in mid-stomach and spreading through the caudad stomach.
    • Strong peristaltic, very tight ring-like constrictions.
    • At the stomach becomes progressively more and more empty, the constrictions begin farther and farther up the body of the stomach.
    • Emptying does not occur because of increased pressure since the increase in volume does not increase pressure much. It is because of the stretching of the wall and subsequent local myenteric refluxes that pyloric pump is accentuated
    • Chyme emerging from the stomach has a pH of approximately 2.

    Gut-associated Lymphoid Tissue

    • GI tract’s immune system.
    • Largest mass of lymphoid tissue in the human body.

    Enterogastric Reflex

    • Factors that activate the enterogastric reflex: Stretching of duodenal wall, irritation of duodenal mucosa, acidic chyme/protein/fat in the duodenum and hypertonic/hypotonic chyme in the duodenum.
    • These factors inhibit the stomach’s contents from emptying into the small intestine.

    Enterogastric Inhibitory Reflexes

    • Sent from the duodenum to the stomach to slow/stop stomach emptying if the volume of the chyme is too much.
    • Mediated by three routs (1) enteric nervous system in gut wall; (2) prevertebral sympathetic ganglia; (3) vagus nerve.
    • All three routes strongly inhibit the pyloric pump propulsive contractions and increase the tone of the pyloric sphincter, resulting in a decrease in stomach emptying.
    • Enterogastric inhibitory reflexes are especially sensitive to presence of irritants and acids in the duodenum.

    Hormones Inhibiting Stomach Emptying

    • Release from the upper intestine and mainly stimulated by fats.
    • Fat chyme releases CCK while acidic chyme releases secretin.
    • GIP is also released in response to fat and carbohydrates.
    • All three hormones decrease stomach emptying.

    Gastroparesis

    • Aka delayed gastric emptying.
    • Partial paralysis of stomach, resulting in food remaining in the stomach for an abnormally long time.
    • Can be caused by vagus nerve damage.
    • Transient gastroparesis may arise as a consequence of type 1 or type 2 diabetes, anorexia nervosa, bulimia nervosa, Parkinson’s disease, mitochondrial disease, abnormal surgery and heavy cigarette smoking.

    Nasogastric Tube Placement

    • For enteral feeling, medication administration, gastric decompression or to allow continuous aspiration of retained gastric contents.

    Gastric Secretion

    • Oxyntic glands: Also known as gastric glands. Secrete HCl, pepsinogen, intrinsic factor and mucus. Found in the body and fundus of the stomach (80%).
    • Pyloric glands: Mainly secrete mucus, but also secrete gastrin. Located in the antrum of the pylorus (the distal 20% of the stomach).
    • Surface mucous cells: Secrete large quantities of viscid mucus. Cover the entire surface of the stomach mucosa. Mucus secretion is affected by aspirin, NSAIDs, PGE 2, adrenalin and stress. The mucus is alkaline.

    Parietal Cells

    • The only cells that secrete HCl, with a pH as low as 0.8.
    • Secretion is under continuous control by endocrine and nervous signals and by enterochromaffin-like cells (ECL cells)

    Enterochromaffin-Like Cells

    • Primary function is to secrete histamine.
    • Lie in the deep recesses of the oxyntic glands.
    • Release histamine in direct contact with parietal cells.
    • Rate of HCl production is directly related to histamine secretion.
    • Stimulated to secrete histamine by gastrin, which is formed in the antrum.
    • Also stimulated by hormones.

    Gastrin

    • Hormone secreted by gastrin cells (G cells) in the pyloric glands in the antrum.
    • Large polypeptide secreted in two forms- G34 and G17 (numbers indicate the number of amino acids). Smaller form is more abundant.
    • Some proteins stimulate G cells to secrete gastrin into the blood, to be transported to ECL cells, causing histamine release which stimulates HCl secretion.

    Somatostatin

    • High acidity in the antrum stimulates somatostatin release by D cells to inhibit meal-stimulated gastrin secretion.

    Vagus Nerve & HCl Secretion

    • Vagus nerve can stimulate Ach release to act directly and indirectly (by stimulating ECL cells) on parietal cells to release HCl.
    • The vagus also acts on G cells via gastrin-releasing peptide) to stimulate gastrin release to stimulate further HCl release.

    Parietal Cells & HCl Formation

    • Contain large branching intracellular canaliculi.
    • HCl is formed at the villus-like projections inside these canaliculi and is then conducted through the canaliculi to the secretory end of the cell.
    • The main driving force for HCl secretion by the parietal cells is the H+-K+ ATPase.
    • Formation Steps: 1. H+ enters from the parietal cell into the canaliculus lumen in exchange for K +, using ATP. K+ tends to leak back into the lumen. 2. At the basolateral end, Na+ is taken out from the parietal cell into the interstitial fluid in exchange for K+, resulting in low intracellular Na+. Therefore Na+ enters the parietal cell from the canaliculus lumen. Hence, most of the K + and Na+ is reabsorbed into the cell cytoplasm and H+ take their place in the canaliculus. 3. Pumping of of H+ out of the cell allows OH- to accumulate within the parietal cell and bind with CO2 to form HCO3- by carbonic anhydrase. This is then transported into the extracellular fluid in exchange for Cl-, which enter the cell. 4. These Cl- are secreted through chloride channels into the canaliculus, binding with H+ to form HCl. This is then secreted outward through the open end of the canaliculus into the lumen of the gland. 5. Water passes into the canaliculus by osmosis due to the extra ions being secreted into the canaliculus. Hence, the final secretion contains water, HCl (150-160mEq/L), KCl (15mEq/L) and a small amount of NaCl.

    Hydrochloric Acid

    • Released at 150mM/L, pH of 0.8, isotonic and 1500cal/L.
    • Functions include: (1) conversion of pepsinogen to pepsin; (2) bactericidal; (3) Fe3+ reduction to Fe2+; (4) secretion and somatostatin release stimulation and (5) chyme formation and protein denaturation.

    Inter-digestive Period

    • Stomach secretes a few millilitres of gastric juice each hour.
    • Almost entirely of the non-oxyntic type, mainly mucus with little pepsin and no acid.

    Emotional Stimuli & Gastric Secretion

    • Emotional stimuli may increase inter-digestive gastric secretion, contributing to stress ulcers.

    Gastrin, CCK, & Secretin

    • All are large polypeptides.
    • Terminal 5 amino acids in gastrin and CCK are the same.

    Pentagastrin

    • Synthetic gastrin composed of the terminal four amino acids to natural gastric plus the amino acid alanine.
    • Has all the same properties as the natural gastrin.

    Chronic Gastritis

    • Stomach lining becomes inflamed.
    • Can cause destruction of parietal cells, which results in achlorhydria (lack of stomach acid secretion) and pernicious anaemia (anaemia from lack of intrinsic factor) due to failure of maturation of RBCs in the absence of vitamin B12 stimulation of the bone marrow.

    Pernicious Anaemia

    • Bacterial overgrowth and B12 deficiency.### Vitamin B12

    • Vitamin B12 (Cobalamin) deficiencies can cause visual changes, numbness, difficulty walking, memory problems, hallucinations, muscle weakness, gait issues, and personality changes.

    • Vitamin B12 is naturally found in animal products like eggs, milk, cheese, meat, fish, and poultry. Some soy products are fortified with vitamin B12.

    • Slight deficiency can lead to anemia, fatigue, mania, and depression.

    • Long-term deficiency can cause irreversible damage to the brain and central nervous system.

    • Vitamin B12 is only produced by bacteria and not found naturally in plant-based foods.

    • Excess vitamin B12 is excreted or stored, with stores lasting up to a year.

    Role of Intrinsic Factor in Vitamin B12 absorption

    • Vitamin B12 attaches to haptocorrin in the saliva, forming a complex resistant to stomach acid.
    • In the small intestine, pancreatic enzymes break down the complex.
    • Vitamin B12 then binds to intrinsic factor, forming a new complex resistant to digestion in the small intestine.
    • This complex is absorbed in the ileum through receptor-mediated endocytosis using cubilin.
    • Vitamin B12 travels to the liver, where it is stored, or transported in the blood attached to transcobalamin II.

    Helicobacter pylori

    • Helicobacter pylori bacteria causes peptic ulcers.
    • It infects the stomach lining, leading to inflammation (gastritis), which is often without symptoms.
    • This can develop into a duodenal or gastric ulcer, leading to bleeding or perforation.

    Pepsinogen Activation

    • Pepsinogen is inactive when secreted.
    • It becomes activated into pepsin by hydrochloric acid (HCl) from the stomach.
    • Pepsin has no digestive activity above a pH of 5.

    Phases of Gastric Secretion

    • Cephalic Phase: Occurs before food enters the stomach. It is stimulated by sight, smell, thought or taste of food. Signals originate from the cerebral cortex and appetite centers in the amygdala and hypothalamus, transmitted through the vagus nerve to the stomach. Accounts for 30% of gastric secretion.
    • Gastric Phase: Occurs when food is in the stomach. Stimulated by long vagovagal reflexes, local enteric reflexes, and the gastrin mechanism. Accounts for 60% of secretion.
    • Intestinal Phase: Occurs when food reaches the duodenum. Accounts for 10% of secretion.

    Inhibition of Gastric Secretion

    • During the early intestinal phase, chyme can cause a slight stimulation of gastric secretion. However, in other phases, inhibition occurs:
      • Reverse Enterogastric Reflex: Food in the small intestine initiates a reflex through the myenteric nervous system, which inhibits gastric secretion. This reflex is triggered by distention, acidity, protein breakdown products, or irritation of the small intestine mucosa.
      • Hormonal Inhibition: Acid, fat, and protein breakdown products, as well as hyperosmotic or hypoosmotic fluids, or irritating factors in the small intestine stimulate the release of secretin, which inhibits gastric secretion. Other hormones like Peptide YY (PYY), vasoactive intestinal polypeptide (VIP), and somatostatin also contribute to inhibition.

    Ghrelin

    • Ghrelin is a hormone produced mainly in the stomach.
    • It stimulates growth hormone release, appetite, and food intake.
    • It's used to treat weight loss and eating disorders.
    • Additionally, ghrelin improves cardiovascular function.

    Arcuate Nucleus of the Hypothalamus

    • The arcuate nucleus of the hypothalamus is the main target of ghrelin and leptin.
    • Ghrelin stimulates neurons expressing neuropeptide Y (NPY) and agouti-related peptide (AgRP), while leptin inhibits these neurons.
    • Ghrelin is an appetite stimulant (orexigenic), and leptin is an appetite suppressant (anorexigenic).

    Neuropeptide Y (NPY)

    • NPY is released in response to ghrelin.
    • It stimulates appetite and increases body weight.

    Gastric Bypass Surgery

    • Used to treat severe obesity.
    • It reduces the size of the stomach, limiting food capacity and caloric intake.
    • Gastric bypass significantly decreases plasma ghrelin levels.

    Pancreas Structure and Function

    • Lies parallel and beneath the stomach.
    • Large compound gland with internal structure similar to salivary glands.
    • Acini : secrete pancreatic digestive enzymes.
    • Ductules and larger ducts: produce sodium bicarbonate solution.
    • Pancreatic duct: transports enzymes and sodium bicarbonate and joins the hepatic duct to empty into the duodenum through the papilla of Vater, controlled by the sphincter of Oddi.

    Pancreatic Juice

    • Secreted in response to chyme in the small intestine.
    • The composition of pancreatic juice is influenced by the food content of the chyme.

    Insulin Secretion

    • Insulin is secreted by the islets of Langerhans, separate from the pancreatic tissue that produces pancreatic juice.

    Sphincter of Oddi

    • Small but strong muscle ring where the bile duct and pancreatic duct meet.
    • Regulates the flow of bile and pancreatic juice into the duodenum.

    Bile Secretion

    • After meals, especially rich or fatty ones, the gallbladder contracts and releases bile.
    • The sphincter of Oddi relaxes, allowing bile flow into the duodenum.
    • Abnormal relaxation of the sphincter of Oddi leads to bile and pancreatic juice accumulation, causing pain and cramping in the upper right abdomen.

    Odditis

    • Inflammation of the sphincter of Oddi.

    Secretin

    • Acidification of the duodenal lumen stimulates secretin release from S cells.
    • This occurs when the pH drops below 4.5, reaching maximum output at pH 3.
    • Secretin promotes the secretion of aqueous sodium bicarbonate solution from ductal cells, increasing pH.
    • This acts as a natural antacid, protecting the small intestine from the acidic gastric juice.

    Pancreatic Enzymes

    • Pancreatic Amylase: digests starches, glycogen, and most carbohydrates (except cellulose) into disaccharides and some trisaccharides.
    • Pancreatic Lipase: digests neutral fat into fatty acids and monoglycerides.
    • Cholesterol Esterase: breaks down cholesterol esters.
    • Phospholipase: separates fatty acids from phospholipids.
    • Trypsin: splits whole proteins into peptides (most abundant pancreatic enzyme).
    • Chymotrypsin: splits proteins into peptides.
    • Carboxypolypeptidase: breaks down some peptides into individual amino acids.

    Enzyme Activation

    • Trypsin, chymotrypsin, and carboxypolypeptidase are secreted as inactive precursors (zymogens).
    • Trypsinogen is activated by enterokinase, secreted by the intestinal mucosa when chyme enters.
    • Activated trypsin activates other zymogens: trypsinogen, chymotrypsinogen, and procarboxypolypeptidase.

    Trypsin Inhibitor

    • Pancreatic cells secrete trypsin inhibitor, preventing activation of trypsin within the cells and ducts.
    • This prevents digestion of the pancreas by its own enzymes.

    Acute Pancreatitis

    • Severe pancreatic damage or a blocked duct leads to the accumulation of pancreatic secretions.
    • Trypsin inhibitor is overwhelmed, causing pancreatic self-digestion and acute pancreatitis.
    • This can be fatal due to shock or lead to long-term pancreatic insufficiency.

    Bicarbonate Secretion

    • Bicarbonate ions and water are the main components of pancreatic juice, secreted by ductal cells.
    • Bicarbonate concentration reaches high levels, neutralizing hydrochloric acid from the stomach.
    • Bicarbonate Secretion Steps:
      1. CO2 from blood enters the cell, combining with water to form carbonic acid, which then breaks down to bicarbonate and hydrogen ions.
      2. Bicarbonate enters the cell with sodium ions.
      3. Bicarbonate is exchanged for chloride at the lumen's edge by secondary active transport. Chloride is recycled back into the lumen.
      4. Hydrogen ions are exchanged for sodium at the basolateral membrane. Sodium enters with bicarbonate, is transported across the membrane, and then drawn into the lumen by the negative voltage.
      5. The overall movement creates osmotic pressure, drawing water into the pancreatic duct.

    Secretin's Role

    • Secretin directly stimulates the ductal cells to secrete bicarbonate ions, with water following to maintain osmotic equilibrium.
    • Secretin increases cAMP in the ductal cells, opening CFTR chloride channels, leading to chloride-bicarbonate exchange.
    • This process depends on CFTR, explaining why cystic fibrosis patients have pancreatic dysfunction due to CFTR mutations.

    Thymosin Alpha 1

    • Being considered as a potential therapy for cystic fibrosis, as it increases residual activity of mutant CFTR channels and promotes proper trafficking of mutant CFTR to the cell membrane.

    Brunner's Glands

    • Found in the first few centimeters of the duodenum.
    • Compound mucous glands that secrete alkaline mucus in response to tactile, irritating stimuli, vagal stimulation, and gastrointestinal hormones (especially secretin).
    • The alkaline mucus protects the duodenum from acidic gastric juice and neutralizes HCl.
    • Brunner's glands also secrete urogastrone, which inhibits acid and digestive juice secretion by parietal and chief cells in the stomach.
    • Sympathetic stimulation inhibits Brunner's glands.

    Cholecystokinin (CCK)

    • Produced by I cells in the small intestinal epithelium.
    • Released into the interstitial space when fatty acids or certain amino acids are present in the intestinal lumen.
    • Release is regulated by CCK-released factor (from paracrine cells) and monitor peptide (from pancreatic acinar cells).
    • CCK promotes the secretion of pancreatic digestive enzymes:
      • Acts as a classic hormone, traveling through the bloodstream to acinar cell CCK1 receptors.
      • Stimulates neural reflex pathways in the pancreas, activating a vagovagal reflex that enhances acinar cell secretion.

    Phases of Pancreatic Secretion

    • Cephalic Phase: Same nervous signals from the brain as in gastric secretion. Acetylcholine is released by vagal nerve endings in the pancreas. This releases moderate amounts of enzymes, responsible for about 20% of total enzyme secretion. However, the secretion doesn't immediately flow into the intestine.
    • Gastric Phase: Nervous stimulation continues, causing 5-10% of pancreatic enzyme release. Little reaches the duodenum due to lack of significant fluid secretion.
    • Intestinal Phase: Copious pancreatic secretion occurs after chyme leaves the stomach, particularly in response to secretin.

    Stimuli for Pancreatic Secretion

    • Acetylcholine: Released from parasympathetic vagus nerve endings and enteric nervous system.
    • Cholecystokinin: Released from the duodenum and jejunum when food enters the small intestine.
    • Secretin: Released from the duodenum and jujunum when highly acidic food enters the small intestine.

    Summary

    • Acetylcholine and CCK stimulate the pancreas to release digestive enzymes.
    • Secretin promotes the secretion of sodium bicarbonate and water, washing enzymes into the duodenum.

    Secretin

    • Secretin is stored as prosecretin in the duodenum and jejunum.
    • Acidic chyme (pH less than 5) causes secretin release and activation.
    • Secretin stimulates the pancreas to release high bicarbonate and low chloride fluid, essential for neutralizing stomach acid and preventing ulcer formation.

    Bile Secretion

    • Between 600 to 1000 ml of bile is produced daily.
    • Key role in fat digestion and absorption:
      • Bile acids emulsify large fat particles, increasing surface area for enzyme activity.
      • Aids in the absorption of fats.
    • Also excretes waste products like bilirubin and cholesterol from the blood.

    Steps in Bile Secretion

    • Step 1: Hepatocytes: Primary bile secretion with high concentrations of bile acids, cholesterol, and organic components into tiny bile canaliculi.
    • Step 2: Bile Ducts: Flowing through the canaliculi, bile moves to terminal bile ducts, then larger ducts, eventually reaching the hepatic duct and common bile duct, where it either directly enters the duodenum or flows into the gallbladder.
    • Step 3: Ductal Epithelium: Water solution of sodium and bicarbonate ions are added to the bile, increasing its volume.
    • Step 4: Secretin Stimulation: Secretin increases this water and bicarbonate solution secretion, which further neutralizes stomach acid.

    Gallbladder

    • Stores bile.
    • Absorbs sodium, chloride, water, and other diffusible substances by active transport.

    Gallbladder Emptying

    • When food enters the upper GI tract, the gallbladder starts to empty, especially when fatty foods reach the duodenum.
    • This is driven by rhythmic contractions of the gallbladder wall.
    • Simultaneously, the sphincter of Oddi relaxes, allowing bile flow.

    Stimuli for Gallbladder Contraction

    • CCK: Most potent stimulus.
    • Acetylcholine: From vagus and enteric nerves, less potent than CCK.

    Bile Acid Formation

    • Precursor: Cholesterol, obtained from the diet or synthesized by the liver during fat metabolism.
    • Conversion: Cholesterol is converted into cholic acid or chenodeoxycholic acid.
    • Conjugation: These acids combine with glycine or taurine to form bile acids.
    • Secretion: Bile salts of these acids are then secreted in bile.

    Bile Acid Actions

    • Detergency/Emulsification: Reduces surface tension, breaking down large fat particles into smaller ones.
    • Micelle Formation: Form small physical complexes called micelles, aiding in absorption.

    Liver Functions

    • Largest organ in the body.
    • Key Functions:
      • Filtration and storage of blood.
      • Metabolism of carbohydrates, proteins, fats, hormones, and foreign chemicals.
      • Bile formation.
      • Storage of vitamins and iron.
      • Production of clotting factors.

    Liver Anatomy

    • Lobule: Basic functional unit.
      • Contains a central vein that drains into hepatic veins, then to the vena cava.
      • Plates of cells radiate from the central vein.
      • Bile canaliculi lie between cells, emptying into bile ducts.
      • Small portal venules receive blood from the GI tract via the portal vein.
      • Hepatic sinusoids lie between the plates, receiving blood from the portal venules and draining to the central vein.
      • Hepatic arterioles supply arterial blood to the septum and many empty directly into the hepatic sinusoids.

    Liver Structure and Function

    • Venous sinusoids are lined by endothelial cells and Kupffer cells, which are resident macrophages that phagocytize bacteria and foreign matter.
    • Spaces of Disse are narrow tissue spaces between endothelial cells and hepatic cells, connecting to lymph vessels.
    • Cirrhosis is the destruction of liver parenchymal cells and their replacement with fibrous tissue, constricting blood vessels and impeding portal blood flow.
    • Non-alcoholic fatty liver disease is a less severe form of fat accumulation and inflammation in the liver, associated with obesity and type II diabetes.
    • Portal hypertension occurs when the portal vein or its branches are blocked, leading to increased pressure in the intestinal capillaries and fluid leakage into the intestines.
    • Liver blood reservoir function allows storage of blood volume up to 30% of total in cases of high pressure in the right atrium.
    • High hepatic vascular pressures cause fluid transudation into the abdominal cavity (ascites) due to increased permeability of sinusoids and high lymph flow.
    • Liver regeneration is rapid after partial hepatectomy or acute liver injury, with hepatocytes replicating until the original size and volume are restored.
    • Hepatocyte growth factor is crucial for liver cell division and growth, produced by mesenchymal cells and rising dramatically after hepatectomy. Other growth factors and cytokines may also contribute.
    • Transforming growth factor-beta inhibits liver cell proliferation and is believed to terminate regeneration.
    • Hepatic macrophage system cleanses the blood by phagocytizing bacteria from the intestines.

    Liver Metabolism

    • Carbohydrate metabolism includes glycogen storage, conversion of galactose and fructose to glucose, gluconeogenesis, and formation of compounds from carbohydrate intermediates.
    • Fat metabolism involves fatty acid oxidation for energy, synthesis of cholesterol, phospholipids, and lipoproteins, and fat synthesis from proteins and carbohydrates.
    • Beta-oxidation of fatty acids occurs primarily in hepatic cells, producing acetyl CoA that can enter the citric acid cycle.
    • Protein metabolism encompasses deamination of amino acids, urea formation, plasma protein synthesis, amino acid interconversions, and synthesis of various compounds from amino acids.
    • Deamination of amino acids removes ammonia from body fluids. High plasma ammonia can lead to hepatic coma.
    • Gamma globulins are formed by plasma cells in lymph tissue, while other plasma proteins are synthesized by hepatic cells.
    • Liver storage function includes vitamins (A, D, and B12), ferritin (iron storage), and coagulation factors (formed with the help of Vitamin K).
    • Detoxification and excretion functions include drug and hormone excretion and calcium excretion in bile.

    Bilirubin Metabolism and Jaundice

    • Bilirubin is a major end product of heme degradation, excreted in bile.
    • When red blood cells die, heme is split into globin and heme.
    • Hemoglobin breakdown forms free iron and a straight chain of four pyrrole nuclei, which is converted to biliverdin then free bilirubin (unconjugated).
    • Unconjugated bilirubin is transported by albumin to the liver, where it is conjugated with glucuronic acid/sulfate, forming bilirubin glucuronide/sulfate, and excreted into the intestines.
    • In the intestines, bilirubin is converted to urobilinogen (highly soluble), some of which is reabsorbed and excreted back into the gut.
    • Urobilinogen is excreted by the kidneys, and in the urine, it becomes urobilin. In feces, it is further oxidized to stercobilin.
    • Jaundice is a yellowish tint of body tissues caused by high bilirubin levels in extracellular fluids.
    • Causes of jaundice include increased red blood cell destruction (hemolytic jaundice), obstruction of bile ducts (obstructive jaundice), and liver cell damage.

    Digestion

    • Hydrolysis is the breakdown of carbohydrates, fats, and proteins by enzymes reacting with water molecules.
    • Carbohydrate digestion starts in the mouth with salivary amylase, continues in the stomach (until acid blocks it), and is completed in the small intestine using pancreatic amylase and enzymes in enterocytes.
    • Protein digestion starts in the stomach with pepsin, continues in the small intestine with pancreatic proteolytic enzymes, and is finalized in the small intestine with enterocyte peptidases, resulting in single amino acids.
    • Fat digestion is primarily carried out by pancreatic lipase after emulsification by bile acids and lecithin, with bile salt micelles transporting the products.
    • Bile salt micelles also transport cholesterol and phospholipids to the small intestine.

    Absorptive Surface Modifications

    • Valvulae conniventes (Folds of Kerckring) are folds in the small intestinal mucosa that increase surface area.
    • Villi and microvilli are structures on the epithelial surface that further enhance surface area for absorption.
    • Pinocytic vesicles are pinched-off portions of the enterocyte membrane involved in absorbing fluids.
    • Actin filaments in the microvilli allow rhythmic contractions to enhance absorption.
    • Water transport occurs via osmosis, both paracellularly and transcellularly.

    Intestinal Fluid and Electrolyte Absorption and Secretion

    • Cholera toxin causes watery diarrhea by preventing down-regulation of water and electrolyte secretion in the small intestine.
    • Hyponatraemia is a common electrolyte abnormality, increasing the risk of death in hospitalized patients.
    • Aldosterone increases sodium, chlorine, water, and other electrolyte absorption.
    • Bicarbonate is secreted in the upper small intestine by the pancreas and must be reabsorbed.
    • The ileum and large intestine secrete bicarbonate ions in exchange for chloride absorption to neutralize acids produced by bacteria.
    • Calcium ions are actively absorbed from the small intestine, particularly the duodenum, regulated by parathyroid hormone and vitamin D.
    • Iron ions are also actively absorbed from the small intestine.### Anaemia Risk Factors
    • Infants who do not receive enough iron in their diet
    • Children during growth spurts
    • Individuals experiencing menstruation or menstrual problems
    • Pregnant women
    • People undergoing chemotherapy
    • Individuals with hemorrhaging ulcers

    Small Intestine Nutrient Absorption

    • Ascorbate and citrate increase iron uptake by acting as weak chelators
    • Potassium, magnesium, and phosphate are actively absorbed
    • Glucose is absorbed through a two-stage co-transport mechanism with sodium
    • Galactose is transported in the same way as glucose
    • Fructose is transported by facilitated diffusion and is converted to glucose within the cell
    • Peptides and amino acids are transported by co-transport with sodium
    • Micelles penetrate into the space between microvilli, releasing monoglycerides and fatty acids into epithelial cells
    • Fatty acids and monoglycerides are incorporated into triglycerides within the cell's smooth endoplasmic reticulum and released as chylomicrons
    • Short- and medium-chain fatty acids are absorbed directly into the portal blood due to their water solubility

    Large Intestine Function

    • The colon actively absorbs most of the remaining water and electrolytes in the chyme
    • The proximal half of the colon is primarily responsible for absorption
    • The distal colon stores feces
    • The colon secretes bicarbonate ions in exchange for chloride ions
      • This helps to neutralize the acidic end products of bacterial activity

    Drug Metabolism

    • The pharmacokinetic process involves absorption, distribution, metabolism, and excretion
    • Biotransformation chemically modifies drugs to facilitate elimination
    • Lipophilic drugs are metabolized more extensively than hydrophilic drugs
    • Drug-metabolizing enzymes (DMEs) are found in various organs, particularly the liver and intestine
    • CYP families, particularly CYP1, 2, and 3, are involved in drug metabolism
    • CYP3A4 is responsible for the metabolism of many drugs and contributes to the poor oral bioavailability of some drugs
    • Drugs undergo oxidation, hydrolysis, or reduction to become more soluble
    • Conjugation, usually with glucose, is another common metabolic process

    Factors Affecting Biotransformation

    • Age, sex, clinical condition, environmental factors, genetics, and species differences all influence drug metabolism
    • Enzyme inducers can shorten the action of drugs or increase the effects of those biotransformed into active agents
    • Enzyme inhibitors can prolong the action of drugs or inhibit the action of those biotransformed into active agents
    • Blockers act on non-microsomal enzymes

    Gastrointestinal Motility

    • Parasympathetic stimulation increases peristalsis and relaxes sphincters
    • Sympathetic stimulation inhibits peristalsis and increases the tone of sphincters
    • The peristalsis reflex, also known as the myenteric reflex, is responsible for coordinated muscle contractions and relaxations
    • The law of the gut describes the downstream direction of peristalsis
    • Peristalsis involves a wave of circular and longitudinal muscle contractions and relaxations
    • Physiological ileus is a temporary absence of motility
    • Paralytic ileus is a prolonged absence of motility
    • The migrating motor complex (MMC) is a cyclical pattern of contractions in the fasted state
      • Phase 1: Quiescence
      • Phase 2: Intermittent, irregular low-amplitude contractions
      • Phase 3: Short bursts of regular, high-amplitude contractions
      • Phase 4: Transition back to quiescense

    IC Valve and Sphincter

    • The ileocecal valve protrudes into the lumen of the cecum and prevents backflow of fecal matter
    • The ileocecal sphincter, located upstream of the valve, slows the emptying of ileal contents
    • The IC valve and sphincter prevent reflux of fecal matter into the small intestine
    • The gastro-ileal reflex promotes chyme passage into the colon

    Colon Function

    • The colon digests and absorbs remaining nutrients and reabsorbs fluids
    • Commensal bacteria have a symbiotic relationship with their human host, metabolizing components of the meal
    • Colonic bacteria also metabolize other endogenic components
    • The colonic mucosa forms haustra, segments created by contractions of the circular muscle layer
    • The primary functions of the large intestine are digestion, absorption, and storage of waste products

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