Physiology & Pharmacology Flashcards
What are the 4 main activities of the alimentary canal?
Motility, secretion , digestion and absorption
What 3 things is secretion required for?
Digestion, protection and lubrication
What is the overall length of GI tract?
7-10m
What are the 4 layers of the GI tract?
1) Mucosa (containing epithelium, lamina própria and muscularis mucosas) 2) Submucosa 3) Muscular externa (circular, longitudinal and enterric plexus) 4) Serosa
Which skeletal muscle is the exception in that is isn’t voluntary?
Upper oesophageal skeletal muscle
What effect does contraction of circular muscle have on the lumen?
Lumen becomes narrower and longer
What effect does contraction of longitudinal muscle have?
Intestines become shorter and fatter
What effect does contraction of muscular mucosal muscle have?
Change in absorptive and secretory area of mucosa (folding) and mixing activity
What is meant by electrical activity occurring as slow waves?
In the stomach, small intestine and large intestine spontaneous electrical activity occurs as rhythmic patterns of membrane depolarization and repolarization that spread from cell to cell via gap junctions - basically determine Basic Electrical Rhythm (BER)
True/False: These slow waves contribute to muscle contraction
False: The slow wave is an underlying electrical process in the GI tract, but action potentials are what cause contraction (though slow waves may contribute to depolarisation)
Which cells drive slow wave electrical activity?
Interstitial cells of Cajal (ICCs) - pacemaker cells interspersed between the far more numerous smooth muscle cells (SMCs)
What is the BER frequency in the stomach?
3 slow waves per minute from the antrum to the body of the stomach
What is the BER frequency in the small intestine?
Approximately 12 waves per minute in the duodenum; approximately 8 waves per minute in the terminal ileum
What is the BER frequency in the large intestine?
Approximately 8 waves per minute in the proximal colon, approximately 16 waves per minute in the distal (sigmoid) colon
Which is the functional implications of having a higher BER in the distal colon than in the proximal?
Causes gentle movement in the aboral to oral direction – promoting retention and absorption, however it is eventually overridden by the mass movement
What is the role of the Myenteric (Auerbach’s) plexus?
Mainly regulates motility and sphincters (more superficial)
What is the role of the Submucous (Meissner’s) plexus?
Mainly modulates epithelia and blood vessels (more deep)
Name 5 key transmitters in the control of peristalsis
- 5-HT, 5-hydroxytryptamine
- ACh, acetylcholine
- NO, nitric oxide
- SP, substance P
- VIP, vasoactive intestinal peptide
Where in the GI tract does the vagal nerve of the parasympathetic system innervate?
Oesophagus, stomach, small intestine and ascending colon
Where in the GI tract does the sacral nerves of the parasympathetic system innervate?
Descending and sigmoid colon and the rectum
What are examples of excitatory influences of the parasympathetic system?
Increased gastric, pancreatic and small intestinal secretion, blood flow and smooth muscle contraction
What are examples of inhibitory influences of the parasympathetic system?
Relaxation of some sphincters, receptive relaxation of stomach
Where does sympathetic innervation of the oesophagus come from?
Post-ganglionic fibres arising from the superior cervical ganglia of the sympathetic chain
Where does sympathetic innervation of the stomach, small intestine and colon come from?
Thoracolumbar outflow
Which are the 3 main abdominal paravertabral ganglia that the sympathetic preganglionic fibres synapse in?
Celiac ganglion, superior mesenteric ganglion, inferior mesenteric ganglion
What are examples of excitatory influences of the sympathetic system?
Increased sphincter tone
What are examples of inhibitory influences of the sympathetic system?
Decreased motility, secretion and blood flow
What are the intrinsic reflexes in the GI tract?
Reflexes which occur entirely in the wall of the GI tract. • Sensory neuron detects event at the mucosa; this modulates the activity of the interneurone, which affects the activity of the effector neutron.
What reflexes underlie peristalsis?
Intrinsic reflexes
What are the short reflexes in the GI tract?
Involve a sensory neuron sending out an afferent fibre which reaches the prevertebral sympathetic ganglia; post ganglionic neutron then signals back to an interneuron which then signals to an effector neuron.
What type of reflex is the intestino-intestinal inhibitory reflex, and what occurs?
Short reflex; if distension is sensed, then this reflex turns on inhibitory stimulation causing the smooth muscle to relax around the area of distension
What are the long reflexes in the GI tract?
Information from the tract is communicated to the CNS.
Sensory neurone signals all the way through the ganglion and onto the parasympathetic fibres in the medulla; this causes increased vagal activity, caused a modulation of the effector neutron.
What type of reflex is the gastroileal reflex, and what occurs?
Long, Neurons which cause increase in gastric activity, cause increased propulsive activity (segmentation) in the empty terminal ileum
What are the major motility patterns of the GI tract?
1) Peristalsis
2) Segmentation
3) Colonic mass movement
4) Migrating motor complex (MMC)
5) Tonic contractions
What is peristalsis?
A wave of relaxation, followed by contraction, that normally proceeds along the gut in an aboral direction – triggered by distension of the gut wall by a bolus
Which transmitters cause contraction of circular muscle behind the bolus, and contraction of longitudinal muscles in front of the bolus in peristalsis?
ACh and substance P
Which transmitters cause relaxation of circular muscle in front of the bolus, and relaxation of longitudinal muscles behind the bolus in peristalsis?
VIP and NO
What is segmentation?
Rhythmic contractions of the circular muscle layer that mix and divide luminal contents (shuffles the food back and forwards breaking it down). Occurs in the small and large intestine in the fed state.
What is haustration?
Segmentation in the large intestine which occurs at a much slower rate
What is colonic mass movement?
Synchronic and powerful sweeping contraction that forces faeces into the rectum – occurs around 3 times a day
What is the Migrating Motor Complex (MMC)?
Powerful sweeping contraction from stomach to terminal ileum (housekeeper function) – typically in the inter-digestive period
What are tonic contractions?
Sustained contractions which are low pressure in organs with a major storage function and high pressure in sphincters
Where is the pyloric sphincter?
Between the pylorus of the stomach and the duodenum
What is the clinical importance of the ileocaecal valve?
Stops bacteria and other colonic contents moving into the ileum
How many deciduous teeth do you have?
20
How many adult teeth do you have?
32
Describe the steps of the oral phase of deglutition?
1) Closing of the mouth
2) Tip of tongue moves to hard palate
3) Back of tongue moves to hard palate, pushing the bolus into the oropharynx
4) Stimulation of mechanoreceptors starts the swallowing reflex (end of voluntary phase)
5) Reflex: Mechanoreceptors cause afferent impulse sent via CN IX and X to pons and medulla
6) Efferent nerve impulses sent via CN VII, IX, X and CI to skeletal muscles of pharynx and larynx
Describe the purpose and steps of the pharyngeal phase of deglutition?
Get bolus into the oesophagus without aspiration into the airways;
1) Inhibition of ventilation
2) Laryngeal muscle close glottis and raise larynx
3) Contractions of superior and middle pharyngeal constrictors propel bolus into hyperpharynx
4) Bolus forces epiglottis over larynx
5) Bolus enters oesophagus through UOS
6) Glottis reopens and ventilation recommences
Describe the steps of the oesophageal phase of deglutition?
1) Circular fibres behind bolus squeeze bolus down
(primary peristaltic wave triggers by the swallowing centre in pons and medulla via the vagus)
2) Longitudinal fibres in front of the bolus shorten the distance of travel
3) LOS opens within 2-3s of the initial swallow
4) Secondary peristaltic wave may be needed for particularly sticky food
What is the name of parotid gland duct and where does it enter the mouth?
Duct of Stensen; opposite second maxillary molar
What is the name of submandibular gland duct and where does it enter the mouth?
Duct of Wharton; under the tongue by the lingual frenulum via sublingual caruncular
What is the name of sublingual gland ducts and where does it enter the mouth?
Ducts of Rivinus which then empty into common Bartholin; connect with Duct of Wharton’s at the sublingual caruncular
What are the 3 main components of salivary glands?
1) External fibrous capsule
2) septa separating lobes and lobules
3) Series of large lobules composed of salivons (functional units)
What are the 3 main components of each salivon of a salivary gland?
1) Secretory acinus
2) Intercalated duct (which lead into…)
3) Striated duct (which unite to form interlobular ducts and excretory ducts)
What is the main type of organic secretion of parotid glands?
Serous secretion by serous cells with a water amylase rich solution (25% of daily secretions)
What is the main type of organic secretions of submandibular glands?
Mixed serous and mucous cells produce a more viscous solution (70% of daily secretions)
What is the main type of organic secretions of sublingual glands?
Mainly mucous cells produce a thick mucous secretion (5% of daily secretions)
In what ways does composition of saliva vary with rate?
- HCO3- concentration increases with rate (as does pH then)
- K+ concentration decreases with rate
What are the 2 stages of saliva formation?
1) Primary secretion by the acing cells (driven by basolateral Na+/K+-ATPase which Cl- efflux being the main movement, as well as Na+ and K+)
2) Secondary modification by duct cells (remove Na and Cl, and add K+ and HCO3 as well as diluting)
What cranial nerves are responsible for parasympathetic stimulation driving normal saliva formation?
Glossopharyngeal (IX) and Facial (VII)
What is the volume capacity of the stomach?
50-100ml
Which cranial nerve controls receptive relaxation of the stomach?
Vagus
What is a unique histological feature of the stomach?
obligue smooth muscle layer in muscular externa, which allows to adjust volume and churn food
Where is the first site of digestion for 1) carbohydrates 2) lipids and 3) proteins?
1) Mouth
2) Mouth
3) Stomach
Which gastric and duodenal factors govern stomach emptying via the strength of the astral wave?
Gastric: rate of emptying is proportional to volume and consistency of chyme. Distension by chyme increase motility due to SM stretch, activity of enteric plexuses, vagus activity and gastrin release
Duodenal: must tell the stomach when it is or isn’t ready for chyme. Emptying is therefore delayed by hormonal (enterogastromes e.g. secretin or CCK) or neuronal (enterogastric reflex) responses. Driver of the are: presence of fat, acidity, hypertonicity and distension.
Where is the oxyntic mucosa (OM) in the stomach and what does it secrete?
Fundus and body; Hydrochloric acid, pepsinogen, intrinsic factor, histamine, mucus
What cell secretes HCl?
Gastic parietal cell
What is the role of HCl in the GI tract?
Activates pepsinogen to pepsin and kills most micro-organisms digested with food
What is the role of intrinsic factor?
Binds Vit B12, allowing absorption in the terminall ileum
What is the role of histamine in the GI tract?
Stimulates HCl secretion (alongside gastrin)
Which cell in the OM secretes pepsinogen?
Gastric chief cells
Which cell on the OM secretes intrinsic factor?
Gastric parietal cells
Which cell in the OM secretes histamine?
Enterochromaffin-like (ECL) cells
Which cell in the OM and PGA secretes mucus?
Goblet cells
Where is the pyloric gland area (PGA) in the stomach and what does it secrete?
Antrum; Gastrin, somatostatin and mucus
What is the role of gastrin?
Stimulates HCl secretion (alongside histamine)
What cell secretes gastrin?
G cells in the gastric antrum (PGA) and the duodenum
What is the role of somatostatin?
Inhibits HCl secretion
What cell in the PGA secretes somatostatin?
Delta cells
How is HCl secreted from the parietal cell, and what pump is mainly involved?
Chloride leaves the cell passively through the canaliculus, while hydrogen is actively pumped out of the cell (due to million fold gradient) by H+-K+-ATPase (proton pump). H+ and chloride then meet and form HCl. The H+-K+-ATPase (proton pump) is a target for drugs treating ulcers.
What are the neuronal controls of HCl secretion from the parietal cells?
Vagus nerve releases ACh which directly acts on the M3 muscarinic receptors on the membrane of the parietal cell. Also act on the ECL cells by activating their M1 muscarinic receptors, causing release of histamine, which act on the H2 histamine receptors on the parietal cell increasing proton pump activity.
What are the hormonal controls which stimulate HCl secretion from the parietal cells?
Gastrin is released from G cells in response to stomach distension, which enters systemic circulation and arrives back at the stomach where it stimulates gastrin receptors on the parietal cells, and also on the ECL cells
What are the hormonal controls which inhibit HCl secretion from the parietal cells?
Somatostatin is released from D cells between meals and cause a decrease in gastrin release.
Prostaglandin E2 provides a protective mechanisms when formed in the GI tract by acting on prostaglandin receptors to inhibit action of ACh, gastrin and histamine (all of which stimulate HCl release)
How does the activation of the proton pump by various secretagogues (ACh, gatrin, histamine) actually occur?
By stimulating their respective receptors on the parietal cell, they cause the physical insertion of the proton pump into the apical canalicular membrane via trafficking and fusion. At rest these pumps are contained inactively in tubulovesicles within the cell
What are the 3 phases of gastric secretion?
1) Cephalic - anticipatory, before food reaches the stomach
2) Gastric - when food is in the stomach
3) Intestinal - when food has left the stomach
What neurotransmitter is released in response to vagal stimulation during the cephalic phase of gastric secretion?
Gastrin-releasing peptide, which acts on G cells to release gastrin (which stimulates parietal cells to release HCl)
What role do enteric neurones have in the cephalic phase of gastric secretion (alongside vagal stimulation)?
Release ACh which:
•Stimulates the parietal cell
•Stimulates the ECL cells to release histamine to act on the parietal cell
•Inhibits the activity of the D cells, to stop them releasing somatostatin
What effect to mechanoreceptors have in the gastric phase of gastric secretion?
Sensing distension, they act on the G cells to release gastrin, and also stimulate enteric neurones which act as in the cephalic phase
What occurs in the intestinal phase of gastric secretion?
Includes factors originating from the small intestine that switch off acid secretion (same factors that reduce gastric motility also reduce gastric secretion)
Secretion of somatostatin resumes
What is the most important drug target in the gastric secretion and why?
Inhibition of proton pump, because if proton pump is inhibited, all secretagogues are inhibited (ACh, gastrin & histamine)
What are the 2 main drug targets in gastric secretion and examples of each?
Proton pump inhibitors - e.g. omeprazole
Histamine H2 receptor antagonists e.g. cimetidine and ranitidine
How do PPIs act on the proton pump?
Irreversible, covalent modification
How do NSAIDs have their negative effects on gastric secretion?
Prostaglandins are produced from arachidonic acid via metabolism through cyclo-oxygenase. NSAIDs act as irreversible inhibitors of cyclo-oxygenase, and therefore NSAIDs block PGE2 formation in the stomach (therefore blocking the protective mechanism and stimulate gastric acid secretion). NSAIDS also decrease mucous and bicarbonate secretion, and mucosal blood flow.
How do prostaglandins provide protection of the mucosa from HCl and pepsin?
- reduce acid secretion (by inhibiting secretagogues)
- increase mucus and bicarbonate secretion (minimise acidity)
- increase mucosal blood flow
What function does the mucous gel layer have?
Forms an important barrier between the acidic lumen and the surface mucous cells, so even though the lumen has a pH of 2, the surface mucous cells remain at a pH of 7. (NSAIDs can break down this gel layer)
What drug type can be given to counteract the harmful effects of NSAIDs, and give and example
PGE1 analogue (acts as endogenous prostaglandin) - e.g. misoprostol
How does H. pylori cause a predisposition to ulcers?
It is within the mucous gel layer where it is protected, and secretes inflammatory agents, weakening the mucosal barrier - leaving the submucosa exposers to HCl and pepsin
PPIs are basic prodrugs, what does this mean?
They are inactive at neutral pH, and are only activated at an acidic pH, such as in the canaliculus in the stomach
What are the indications for PPIs?
1) Peptic ulcers
2) GORD
3) Zollinger-Ellison syndrome
What are sucralfate and bismuth chelate examples of?
Mucosal strengtheners
What are the 2 main types of digestion which occur in the SI?
1) Luminal digestion - mediated by pancreatic enzymes
2) Membrane digestion - enzymes not produced by the pancreas, present on the apical membrane of the enterocytes (brush border)
Digestion + absorption =
Assimilation
What are the 5 main mechanisms of digestion?
1) None (some substances are already digestible)
2) Luminal hydrolysis - e.g. protein > amino acids
3) Brush border hydrolysis
4) Intracellular hydrolysis
5) Luminal hydrolysis followed by intracellular re-synthesis e.g. triglycerides are broken down in the lumen, but are then recombined once in the cells – chylomicrons
What are oligosaccharidases?
Integral membrane proteins with a catalytic domain that faces the lumen of the GI tract e.g. lactase, maltase, sucrase
Where does the absorption of carbohydrate digestion (glucose, galactose and fructose) occur?
Duodenum and jejunum
How does protein digestion occur in the stomach?
1) HCl denatures the proteins by weakening the bonds between AAs
2) Pepsin cleaves the proteins into peptides
What are the 4 main pathways of protein digestion?
1) Peptide transported straight out of the enterocyte without hydrolysis
2) Luminal enzymes > through apical membrane > basolateral membrane > blood
3) Luminal enzymes > brush border enzymes > through apical membrane > basolateral membrane > blood
4) Luminal enzymes > through apical membrane > intracellular hydrolysis > basolateral membrane > blood
What are the 5 pancreatic proteases which are activated and used in the duodenum?
Trypsin Chymotrypsin Elastase Procaroxypeptidase A Procaroxypeptidase B
What is an endopeptidase, and which protease are examples of these?
Attack peptide bonds between internal AAs; pepsin, trypsin, chymotrypsin, elastase
What is an exopeptidase, and which protease are examples of these?
Procaroxypeptidase A, Procaroxypeptidase B
Amino acid transport mechanisms at the brush border and basolateral membrane can be of which 2 forms?
1) Na+ dependent (secondary active transport coupled to Na ‘uphill’)
2) Na+ independent