Physiology & Pharmacology Flashcards
(279 cards)
1
Q
What are the 4 main activities of the alimentary canal?
A
Motility, secretion , digestion and absorption
2
Q
What 3 things is secretion required for?
A
Digestion, protection and lubrication
3
Q
What is the overall length of GI tract?
A
7-10m
4
Q
What are the 4 layers of the GI tract?
A
1) Mucosa (containing epithelium, lamina própria and muscularis mucosas) 2) Submucosa 3) Muscular externa (circular, longitudinal and enterric plexus) 4) Serosa
5
Q
Which skeletal muscle is the exception in that is isn’t voluntary?
A
Upper oesophageal skeletal muscle
6
Q
What effect does contraction of circular muscle have on the lumen?
A
Lumen becomes narrower and longer
7
Q
What effect does contraction of longitudinal muscle have?
A
Intestines become shorter and fatter
8
Q
What effect does contraction of muscular mucosal muscle have?
A
Change in absorptive and secretory area of mucosa (folding) and mixing activity
9
Q
What is meant by electrical activity occurring as slow waves?
A
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)
10
Q
True/False: These slow waves contribute to muscle contraction
A
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)
11
Q
Which cells drive slow wave electrical activity?
A
Interstitial cells of Cajal (ICCs) - pacemaker cells interspersed between the far more numerous smooth muscle cells (SMCs)
12
Q
What is the BER frequency in the stomach?
A
3 slow waves per minute from the antrum to the body of the stomach
13
Q
What is the BER frequency in the small intestine?
A
Approximately 12 waves per minute in the duodenum; approximately 8 waves per minute in the terminal ileum
14
Q
What is the BER frequency in the large intestine?
A
Approximately 8 waves per minute in the proximal colon, approximately 16 waves per minute in the distal (sigmoid) colon
15
Q
Which is the functional implications of having a higher BER in the distal colon than in the proximal?
A
Causes gentle movement in the aboral to oral direction – promoting retention and absorption, however it is eventually overridden by the mass movement
16
Q
What is the role of the Myenteric (Auerbach’s) plexus?
A
Mainly regulates motility and sphincters (more superficial)
17
Q
What is the role of the Submucous (Meissner’s) plexus?
A
Mainly modulates epithelia and blood vessels (more deep)
18
Q
Name 5 key transmitters in the control of peristalsis
A
- 5-HT, 5-hydroxytryptamine
- ACh, acetylcholine
- NO, nitric oxide
- SP, substance P
- VIP, vasoactive intestinal peptide
19
Q
Where in the GI tract does the vagal nerve of the parasympathetic system innervate?
A
Oesophagus, stomach, small intestine and ascending colon
20
Q
Where in the GI tract does the sacral nerves of the parasympathetic system innervate?
A
Descending and sigmoid colon and the rectum
21
Q
What are examples of excitatory influences of the parasympathetic system?
A
Increased gastric, pancreatic and small intestinal secretion, blood flow and smooth muscle contraction
22
Q
What are examples of inhibitory influences of the parasympathetic system?
A
Relaxation of some sphincters, receptive relaxation of stomach
23
Q
Where does sympathetic innervation of the oesophagus come from?
A
Post-ganglionic fibres arising from the superior cervical ganglia of the sympathetic chain
24
Q
Where does sympathetic innervation of the stomach, small intestine and colon come from?
A
Thoracolumbar outflow
25
Which are the 3 main abdominal paravertabral ganglia that the sympathetic preganglionic fibres synapse in?
Celiac ganglion, superior mesenteric ganglion, inferior mesenteric ganglion
26
What are examples of excitatory influences of the sympathetic system?
Increased sphincter tone
27
What are examples of inhibitory influences of the sympathetic system?
Decreased motility, secretion and blood flow
28
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.
29
What reflexes underlie peristalsis?
Intrinsic reflexes
30
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.
31
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
32
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.
33
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
34
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
35
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
36
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
37
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
38
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.
39
What is haustration?
Segmentation in the large intestine which occurs at a much slower rate
40
What is colonic mass movement?
Synchronic and powerful sweeping contraction that forces faeces into the rectum – occurs around 3 times a day
41
What is the Migrating Motor Complex (MMC)?
Powerful sweeping contraction from stomach to terminal ileum (housekeeper function) – typically in the inter-digestive period
42
What are tonic contractions?
Sustained contractions which are low pressure in organs with a major storage function and high pressure in sphincters
43
Where is the pyloric sphincter?
Between the pylorus of the stomach and the duodenum
44
What is the clinical importance of the ileocaecal valve?
Stops bacteria and other colonic contents moving into the ileum
45
How many deciduous teeth do you have?
20
46
How many adult teeth do you have?
32
47
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
48
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
49
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
50
What is the name of parotid gland duct and where does it enter the mouth?
Duct of Stensen; opposite second maxillary molar
51
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
52
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
53
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)
54
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)
55
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)
56
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)
57
What is the main type of organic secretions of sublingual glands?
Mainly mucous cells produce a thick mucous secretion (5% of daily secretions)
58
In what ways does composition of saliva vary with rate?
- HCO3- concentration increases with rate (as does pH then)
| - K+ concentration decreases with rate
59
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)
60
What cranial nerves are responsible for parasympathetic stimulation driving normal saliva formation?
Glossopharyngeal (IX) and Facial (VII)
61
What is the volume capacity of the stomach?
50-100ml
62
Which cranial nerve controls receptive relaxation of the stomach?
Vagus
63
What is a unique histological feature of the stomach?
obligue smooth muscle layer in muscular externa, which allows to adjust volume and churn food
64
Where is the first site of digestion for 1) carbohydrates 2) lipids and 3) proteins?
1) Mouth
2) Mouth
3) Stomach
65
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.
66
Where is the oxyntic mucosa (OM) in the stomach and what does it secrete?
Fundus and body; Hydrochloric acid, pepsinogen, intrinsic factor, histamine, mucus
67
What cell secretes HCl?
Gastic parietal cell
68
What is the role of HCl in the GI tract?
Activates pepsinogen to pepsin and kills most micro-organisms digested with food
69
What is the role of intrinsic factor?
Binds Vit B12, allowing absorption in the terminall ileum
70
What is the role of histamine in the GI tract?
Stimulates HCl secretion (alongside gastrin)
71
Which cell in the OM secretes pepsinogen?
Gastric chief cells
72
Which cell on the OM secretes intrinsic factor?
Gastric parietal cells
73
Which cell in the OM secretes histamine?
Enterochromaffin-like (ECL) cells
74
Which cell in the OM and PGA secretes mucus?
Goblet cells
75
Where is the pyloric gland area (PGA) in the stomach and what does it secrete?
Antrum; Gastrin, somatostatin and mucus
76
What is the role of gastrin?
Stimulates HCl secretion (alongside histamine)
77
What cell secretes gastrin?
G cells in the gastric antrum (PGA) and the duodenum
78
What is the role of somatostatin?
Inhibits HCl secretion
79
What cell in the PGA secretes somatostatin?
Delta cells
80
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.
81
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.
82
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
83
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)
84
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
85
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
86
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)
87
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
88
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
89
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
90
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)
91
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
92
How do PPIs act on the proton pump?
Irreversible, covalent modification
93
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.
94
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
95
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)
96
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
97
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
98
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
99
What are the indications for PPIs?
1) Peptic ulcers
2) GORD
3) Zollinger-Ellison syndrome
100
What are sucralfate and bismuth chelate examples of?
Mucosal strengtheners
101
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)
102
Digestion + absorption =
Assimilation
103
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
104
What are oligosaccharidases?
Integral membrane proteins with a catalytic domain that faces the lumen of the GI tract e.g. lactase, maltase, sucrase
105
Where does the absorption of carbohydrate digestion (glucose, galactose and fructose) occur?
Duodenum and jejunum
106
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
107
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
108
What are the 5 pancreatic proteases which are activated and used in the duodenum?
```
Trypsin
Chymotrypsin
Elastase
Procaroxypeptidase A
Procaroxypeptidase B
```
109
What is an endopeptidase, and which protease are examples of these?
Attack peptide bonds between internal AAs; pepsin, trypsin, chymotrypsin, elastase
110
What is an exopeptidase, and which protease are examples of these?
Procaroxypeptidase A, Procaroxypeptidase B
111
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
112
How to oligopeptides move into the enterocytes?
PepT1 transporters coupled to H+
113
What are the 3 phases of lipid digestion?
1) Lingual phase - mouth via salivary secretions
2) Gastric phase - heat and movement of stomach help breakdown large globules into smaller globules
3) Small intestine - most important - emulsification by blue and hydrolysis by pancreatic lipase
114
What neurotransmitter stimulates bile secretion from the gallbladder and the opening of the Sphincter of Oddi?
Cholecystokinin (CCK)
115
What is a sign of lipid malabsorption?
Steatorrhoea (fat in faeces)
116
What is the purpose of bile salts?
Increases surface area for attack by pancreatic lipase by emulsifying the lipid into more, smaller micelles
117
What is the function of colipase?
As a consequences of emulsification, bile salts block access of the lipase to the triglyceride within the micelle. Colipase is therefore an amphipathic polypeptide secreted with lipase by the pancreas – binds to bile salts and lipase allowing access to tri- and di-glycerides
118
What are the final products of lipid digestion?
Free fatty acids, monoglcerides, cholesterol, bile salts and phospholipids (stored in and released from micelles)
119
What is the outcome of short/medium fatty acids after digestion?
Mixed micelle containing the fatty acids and monoglycerides attach to the apical membrane of the enterocytes and the fatty acids transfer across. Small/medium fatty acids diffuse through the enterocyte straight into the villus capillaries.
120
What is the outcome of long chain fatty acids and monoglycerides after digestion?
Long chain fatty acids and monoglycerides are resynthesises into triglycerides in the ER along with cholesterol, forming chylomicrons, which entire the central lacteal of the villus where it carried to the systemic circulation via the thoracic duct
121
How is Ca2+ absorbed?
By both passive transport, and active transport mechanisms regulated by calcitriol and parathyroid hormone
122
Which form of iron is and isn't absorbable?
Ferrous (Fe2+) is, but ferric (Fe3+) is not
123
How is Vit B12 absorbed?
1) Haptocorin released from salivary glands binds with Vit B12 in stomach. 2) Pancreatic proteases then digest haptocorin in SI, releasing Vit B12, allowing it to bind to intrinsic factor. 3) This Vit B12-intrinsic factor complex is then absorbed in terminal ileum but endocytosis
124
Which vitamins are fat soluble and how are they absorbed?
Vit A, D, E and K; they are incorporated into micelles and then chylomicrons =to be distributed by intestinal lymphatics
125
Which vitamins are water soluble and how are they absorbed?
B couplex vitamines (except B12), C and H; specific transport processes in apical membrane similar to monosaccharides and amino acids, either Na+ independent or dependent
126
What BMI range is classed as underweight?
127
What BMI range is classed as normal?
18.5 -24.9
128
What BMI range is classed as overweight?
25-29.9
129
What BMI range is classed as obese?
30-39.9
130
What BMI range is classed as morbidly obese?
>40
131
Why is it difficult to lose weight once it has been gained?
Long term obesity induces brain reprogramming meaning that your brain views the extra weight (fat) as normal & dieting as threat to body survival such as starvation i.e defends new weight by implementing compensatory process etc
132
What 3 basic concepts underlie the control system of the brain on energy balance and weight?
1) Satiety signalling
2) Adiposity negative feedback signalling
3) Food reward
133
Satiety
period of time between termination of one meal and the initiation of next
134
Adiposity negative feedback signalling
The body telling the brain about the level of fat stores
135
What peptide signals are involved in satiation (reduce food intake between meals)?
- Cholecystokinin (CCK)
- Peptide YY
- Glucagon-like Peptide 1 (GLP-1)
- Oxyntomodulin (OXM)
- Obestatin
136
Where is CCK secreted from?
Secreted from enteroendocrine I cells in duodenum and jejunum
137
Where is Peptide YY secreted from and what does it do?
Endocrine mucosal L cells of GI tract; inhibits gastric motility, slows emptying and reduces food intake (acts on hypothalamus)
138
Where does CCK signal to?
Signals via sensory nerves to hindbrain and stimulates hindbrain directly (nucleus of solitary tract (NTS)).
139
Where is GLP-1 secreted from?
Secreted from L cells throughout the gut in response to food ingestion;
140
Where is oxyntomodulin secreted from and what does it do?
Released from oxyntic cells of small intestine after meal; Acts to suppress appetite
141
Where is obestatin secreted from and what does it do?
Released from cells lining stomach/small intestine; Suggested to reduce food intake – may act to antagonise the actions of ghrelin
142
Which peptide acts as the hunger signal?
Ghrelin
143
Which cells produce ghrelin?
Gr cells in oxyntic glands in stomach, and also in the SI and pancreas etc
144
Which two hormones report fat status to the brain?
Leptin and Insulin
145
Where is leptin made?
Fat cells
146
What happens in the Ob/Ob mousey?
Reduced leptin which mimics starvation and causes unrestrained appetite
147
What happens in the Db/db mousey?
No receptor to leptin so complete loss of leptin signalling causes severe obesity.
148
What role does insulin play on adiposity signals?
High levels of insulin inhibits food intake and decreases fat levels
149
What role does leptin play on adiposity signals?
Low levels of leptin signal low levels of fat stores, so increase appetite
150
When are leptin injections an appropriate choice for anti-obesity treatment?
When a contributor to the obesity is low circulating leptin levels
151
Name 4 types of drugs which can be used for the treatment of obesity, plus examples
1) Noradrenergics e.g. diethylpropion or phentermine (appetite suppressants acting to inhibit NA uptake)
2) Serotonergics e.g. fenfluramine (appetite suppressants acting on 5-HT system)
3) Fen-Phen (combination of phentermine and fenfluramine)
4) Orlistat - inhibits pancreatic lipase decreasing triglyceride absorption
152
What is the evolutionary purpose of nausea and vomiting/diarrhoea?
Protection against food poisoning (along with olfactory cues of that macro polo's being 'bad')
153
Stomach contraction doesn't drive vomiting, as the stomach, oesophagus and sphincters remain relaxed - so what does drive vomiting?
Neuronal control: Vomiting is co-ordinated by the vomiting centre (VC) in the medulla oblongata
154
What are the 5 steps that occur in vomiting?
1. Slow wave activity (propulsive forces moving contents from the oral to anal direction) must be suspended
2. Peristaltic activity then occurs in the opposite direction
3. Airways must then be protected from aspirating vomitus by suspending breathing, and the glottis sealing off the airways
4. LOS relaxes as the diaphragm and abdominal wall contracts. Diaphragm then pushes down which contracts the stomach, and propels the contents out
5. Gastric contents then eject through the UOS and out of the mouth
155
What are the associated events of nausea (not vomiting)?
1) Contraction of upper SI, followed by contraction of pyloric sphincter and pyloric region of stomach
2) Movement of content of upper jejunum, duodenum and pyloric regions into the body and funds of the stomach
3) Relaxed lower and upper oesophageal sphincters and oesophagus (to allow possibility of vomiting)
156
What is the main pathway for stimuli to induce vomiting?
1) Toxic materials etc cause irritation of the gut mucosa
2) Enterochromaffin cells in the mucosa store serotonin (5-hT) which is released on irritation
3) It stimulates local afferent fibres of the vagus nerve via 5-hT 3 receptors to the chemoreceptor trigger zone (CTZ) and the NTS
4) These then stimulate the vomiting centre
157
What are the 4 alternative pathways for vomiting to be induced?
- Absorbed toxins etc in the blood can be detected directly in the CTZ
- Mechanical stimulation in the pharynx and other pathologies stimulate the vagus also
- With motion sickness, the vestibular centre is disturbed which signal to CTZ via vestibular nuclei
- Stimuli within CNS with pain, fear etc signal through cortex and limbic system to medulla > vomiting centre
158
What are the physical changes that occur with vagal motor outputs of vomiting?
* Longitudinal muscle contracts producing shortening of the oesophagus shortening the pathway for vomitus
* Stomach relaxes
* Small intestine contracts as a large retrograde contraction moves contents retrograde
159
What are the physical changes that occur with somatic neurone stimulation in vomiting?
Contraction of anterior abdominal muscles and diaphragm
160
What are the physical responses that occurs as a result of mixed efferent input?
* Vasoconstriction of the skin producing pallor
* Increase in heart rate
* Increased secretion of salivary glands
* Constriction of the sphincters of bladder and anus (to avoid voiding unintentionally, oops)
161
What can be the consequences of severe vomiting?
- Dehydration
- Loss of gastric protons and chloride (causes hypochloraemic metabolic alkalosis, loss of protons raising of blood pH) - systemic alkalosis
- Hypokalaemia - proton loss is accompanied by potassium excretion
- Rarely, loss of duodenal bicarbonate may cause metabolic acidosis
- Rarely, eosophageal damage (Mallory-Weiss tear)
162
Why does cancer chemotherapy and radiotherapy cause nausea?
Release of 5-HT and substance P from enterochromaffin cells in the gut, reinforced by the released of substance P which stimulates vagal afferent fibres
163
Which drugs can cause nausea?
* Chemotherapy (e.g. cisplatin, doxorubicin) and radiotherapy
* Operations involving the administration of a general anaesthetic
* Agents which stimulate dopamine release (e.g. levodopa used in Parkinson’s disease) -Dopamine D2 receptors are prevalent in the CTZ
* Morphine and other opiate analgesics
* Cardiac glycosides (e.g. digoxin)
* Drugs enhancing 5-HT function (e.g. SSRIs)
164
What are the6 major classes of anti-emetic drugs?
- 5-HT3 receptor antagonists – ‘setrons’
- Muscarinic acetylcholine receptor antagonists
- Histamine H1 receptor antagonists
- Dopamine Receptor Antagonists
- NK1 receptor antagonists
- Cannabinoid (CB1) receptor agonists
165
What anti-emetics are ondansetron and palonosetron examples of?
5-HT3 receptor antagonists – ‘setrons’
166
What anti-emetics are hyosine /scopolamine examples of?
Muscarinic acetylcholine receptor antagonists
167
What anti-emetics are cyclizine and cinnarizine examples of?
Histamine H1 receptor antagonists
168
What anti-emetics are domperidone and metoclopramide examples of?
Dopamine Receptor Antagonists
169
What anti-emetics is aprepitant examples of?
NK1 receptor antagonists
170
What anti-emetics is nabilone examples of?
Cannabinoid (CB1) receptor agonists
171
What first line anti-emetics would you use for chemotherapy and radiation-induced emesis (particularly in the acute phase) and post-operative nausea and vomiting?
5-HT3 receptor antagonists – ‘setrons’ (e.g. ondansetron, palonosetion) and Dopamine Receptor Antagonists (e.g. domperidone and metoclopramide)
172
How do 5-HT3 receptor antagonists (e.g. ondansetron, palonosetron) work?
Block peripheral and central 5-HT3 receptors, which are located in terminals at the primary central afferents of the vagus nerve, and signal to the area posrema and nucleus tractus solitaris in the brainstem. These receptors can be stimulated when 5-Ht is released by the entrochromaffin cells in response to pretty much any disturbance of the mucosa eg. Chemotherapy
173
What anti-emetics would you use for motion sickness?
Muscarinic acetylcholine receptor antagonists (e.g. hyosine /scopolamine) and Histamine H1 receptor antagonists (e.g. cyclizine, cinnarizine + many others)
174
How long and wide is the small intestine?
6m long and 3.5cm diameter
175
What lengths are the duodenum, jejunum and ileum?
Duodenum ~25 cm
Jejunum ~2.5 m
Ileum ~ 3 m
176
Which 3 features of the small intestine increase its surface area for absorption?
* Large circular folds (of Kerckring/plicae circularis)
* Villi (1-2mm in length)
* Microvilli (the brush border/apical membrane)
177
Which hormones does the SI secrete?
- Gastrin
- CCK
- Secretin
- Motilin
- Glucagon-like Insulinotropic peptide (GIP) aka gastric inhibitory peptide
- GLP-1
- Gherkin
178
What triggers the release of CCK?
Released in proportion to lipids and proteins in meals
179
What does GLP-1 do?
Inhibits gastric emptying and reduces food intake (acts on hypo and NTS)
180
Which cells secrete secretin?
S cells of the duodenum
181
Which cells secrete motion?
M cells of duodenum and jejunum
182
What is the function of motilin?
Responsible for migrating myoelectric complex
183
Which cells secrete Glucagon-like insulinotropic peptide (GIP)
aka gastric inhibitory peptide)?
K cells of duodenum and jejunum
184
When is gherkin produced?
During times of fasting and hyperglycaemia
185
succus entericus
'juice of the intestine'
186
What does succus entericus contain and how much of it is secreted a day?
• mucus – for protection/lubrication (from goblet cells)
• aqueous salt - for enzymatic digestion (mostly from the crypts of Lieberkühn)
• no digestive enzymes;
2 litres a day
187
Which channel is mostly responsible for the movement of chloride in SI secretions?
Cystic fibrosis transmembrane conductance regulator (CFTR)
188
How long does digestion in the SI take?
3-5hrs
189
What triggers the gastroileal reflex?
Gastrin from the stomach
190
What makes up the exocrine and and endocrine secretions of the pancreas?
Exocrine: Pancreatic juice )(digestive enzymes + aqueous sodium bicarbonate)
Endocrine: glucagon, insulin and somatostatin
191
Endocrine secretions go to...
Bloodstream
192
Exocrine secretions go to...
Ducts
193
What is the pathway of pancreas juice?
Terminal acini -> drain into ductules -> progressively larger ducts -> pancreatic duct --> duodenum via sphincter of Oddi
194
Where are pancreatic enzymes stored?
Secretary granules in the acinar cells
195
What are the 3 main classes of pancreatic enzymes?
Proteases, amylases and lipases
196
Zymogens
Inactive proenzymes (i.e. pancreatic proteases are stored as zymogens)
197
What are the 3 main proenzyme proteases of the pancreas?
Trypsinogen, chymotrypsinogen and procarboxypeptidases A and B
198
What activates trypsinogen into trypsin?
A brush border enzyme called Enterokinase. Once activated, trypsin can then act back in trypsinogen to activate it (autocatalysis)
199
What activates chymotrypsinogen and procarboxypeptidases A and B into chymotrypsin and carboxypeptidases A and B?
Trypsin
200
True/False: pancreatic lipase and amylase are stored and secreted in their active form
True
201
What are the 3 main functions of the alkaline fluid secreted by the pancreas?
1) Neutralises the acidic chyme coming into the duodenum from the stomach
2) Provides the optimum pH for the previous pancreatic enzymes
3) Also lubricates and protects the mucosa from erosion by the digestive acid
202
Which receptor and channel are responsible for the secretion of bicarbonate in the pancreas, and what is an example of pathology of this?
The Cl-/HCO3- exchanger, exchanges chloride inwards for bicarbonate outward, and the Chloride is supplied by the CFTR channel, where it is able to be recycles back out of the cell, in order to be exchanged again. In cystic fibrosis, there is a mutation in this channel so CF pts also have pancreatic insufficiency
203
What are the 3 phases of pancreatic secretion?
1) Cephalic
2) Gastric - gastric distension evokes a vasovagal reflex causing parasympathetic stimulation of acinar and duct cells
3) Intestinal - triggered by arrival of chyme in duodenum
204
Which 2 hormones are associated with the intestinal phase of pancreatic secretion?
Secretin and CCK (secreted from the SI)
205
What triggers the release of secretin and what is its role?
Release from the S cells is triggered by acidic chyme entering the duodenum; It arrives at the pancreatic duct cells which stimulates the secretion of the aqueous bicarbonate solution into the duodenal lumen
206
What triggers the release of CCK and what is its role CCK?
CCK release from the I cells is triggered by fat and protein in the duodenum; CCK goes into the blood stream, arrives at the pancreas and stimulates pancreatic acinar cells which stimulates the secretion all digestive enzymes, but most importantly given what the stimuli are: proteases and lipases
207
What length and width is the large intestine?
1.5m long and 6cm wide
208
What are the principle functions of the ascending and transverse colon?
Fluid reabsorption and bacterial fermentation, such as of carbohydrate
209
How much ileocaecal material does the large intestine receive a day?
1000ml
210
What controls the ileocaecal valve?
Vagus nerve, sympathetic nerve and enteric neurones
211
What are the principle functions of the descending and sigmoid colon?
Final drying out phase – desiccation- and storage
212
What weight of faeces are eliminated a day? (yep, this is your life now)
150g
213
What is faeces composed of? (yep, this is happening)
- 100ml of water
- 50g solid including cellulose
- bacteria (33% dry weight)
- bilirubin
- small amount of salt
214
What is the only true excretory material in the faeces, and what are the rest?
Bilirubin is the only true excretory material, rest are ejestatory
215
What are the 3 patterns of motility in the large intestine?
1) Haustration (non-propulsive segmentation)
2) Peristaltic propulsive movements (mass movement)
3) Defaecation (periodic egestion)
216
Haustra
Saccules (bumbs of the large intestine) caused by contraction of the circular muscle
217
What is haustration?
Similar to segmentation in function, but much lower frequency. These periodically move retrograde slowly and contributes to long transit time (16 – 48 hours) – permitting full reabsorption of water and ions
218
Taenia coli
The outer longitudinal muscle layer of the large intestine is comprised of these three bands
219
What is mass movement in the large intestine?
Simultaneous contraction of large sections of the circular muscle of the colon (haustra disappear) - drives faeces into distal regions
• Occurs about one to three times daily
220
What is the defecation reflex?
- When mass movement pushes faecal matter into the rectum this causes passive distention of the smooth muscle of the rectum wall. If sufficient, it can trigger active contraction of the smooth muscle wall, this in turn leads to the relaxation of the smooth muscle of the internal anal sphincter
• Rectosphincteric reflex.
221
Which nerves are responsible for the defecation reflex?
Pelvic nerves (parasympathetic)
222
Following the defecation reflex, if defecation is appropriate - what happens?
Relaxation of the external anal sphincters occur allowing defecation
• Often assisted by contraction of the abdominal muscles, whilst breathing against a closed glottis
• Both helps increase the intrabdominal pressure which compresses the intestines and aids defecation
223
Following the defecation reflex, if defecation is inappropriate - what happens?
The external anal sphincter contracts
• This causes the rectal smooth muscle to gradual relax, the urge to deficate subsides and only returns once more faecal matter enters the rectum
224
What are the functions of commensal bacteria?
* Increase intestinal immunity by competition with pathogenic microbes
* Promote motility by providing bulk and help maintain mucosal integrity
* Synthesise vitamin K2 and free fatty acids (from carbohydrate) that are absorbed
* Activate some drugs (e.g. used in treatment of IBD)
225
What occurs (fundamental overview) in constipation?
Presence of hard dried faeces within the colon, results from delay in defaecation, meaning it is present in the colon for longer, resulting in enhanced absorption of H2O
226
What are some of the causes of constipation (functionally?
* ignoring, or suppressing, the urge to defaecate (due to inconvenient timing or avoidance due to pain from fissures/haemorrhoids)
* decreased colonic motility
* obstruction of faecal movement
* impairment of motility/defaecation reflex (e.g. Hirschprung disease, involving absence of a section of the enteric nervous system)
227
What is the difference between laxatives and purgatives?
- Laxatives are agents that are used to treat constipation
- Purgatives are agents that cause purging, or cleansing, of the bowels by promoting evacuation, e.g. before abdominal surgery or colonoscopy
228
When should neither laxatives or purgatives be used?
When there is physical obstruction to the bowel
229
What are 3 indications for laxatives?
* When ‘straining’ is potentially damaging to health (e.g. patients with angina), or when defaecation is painful (e.g. haemorrhoids)
* To clear the bowel before surgery, or endoscopy
* To treat drug-induced constipation, or constipation in bedridden, or elderly patients
230
What do laxatives fundamentally do?
Increase peristalsis and/or soften faeces, assisting evacuation
231
What are the 4 main groups of laxatives?
1) Bulk laxatives
2) Osmotic laxatives
3) Faecal softeners
4) Stimulant purgatives
232
What to bulk laxatives do?
Simply bulk up the volume of the stool, which stimulates the enteric system which promotes peristalisis
233
What to osmotic laxatives do?
Maintain or draw water into the GI tract and so bulk the faeces via water rentention
234
What do faecal softeners do?
Soften and lubricate the faeces to make them easier to pass
235
What so stimulant purgatives do?
Stimulate the enteric system
236
What is an example of a osmotic laxative?
Magnesium sulphate/hydroxide or lactulose (oral) or sodium citrate (rectally)
237
What is an example of faecal softeners?
Docusate sodium (oral) or arches oil (enema)
238
What is an example of stimulant purgatives?
Bisacodyl or sodium picosulfate
239
What drugs should be used for acute attacks of IBD?
Glucocorticoids (e.g. prednisilone, budenoside)
240
What drugs should be used for maitnence and mild IBD?
Aminosalicylates e.g. sulfasalazine, mesalazine, olsalazine
241
What drives absorption of water in the GI tract?
Its a passive process driven by the transport of solutes (particularly Na+) from the lumen of the intestines to the bloodstream
242
How many litres of fluid enter and absorbed from the GI tract a day?
9.3 litres enter the tract, 8.3l are absorbed in the SI and 900ml are absorbed from the large intestine
243
What is the definition of diarrhoea?
Loss of fluid and solutes from the GI tract in excess of 500 ml per day (normally excrete 100ml)
244
What are the 2 routes that water may take in absorption?
via 1) transcellular (mediated by aquaporins on apical/basolateral membranes), or 2) paracellular (via tight junctions), routes
245
As water reabsorption tends to follow electrolytes, what are the principal mechanism of Na+ reabsorption and where do they occur?
1) Na+glucose co-transport - small intestine (post-prandial)
2) Na+/H+ exchange - duodenum and jejunum (due to high HCO3- conc)
3) Parallel Na+/H+ and Cl-/HCO3- exchange - ileum and proximal colon (only one regulated by cAMP, cGMP and Ca2+)
4) Epithelial Na+ channels (ENaC) - distal colon (regulated by aldosterone)
246
What are the 2 main mechanisms of postprandial (after a meal) Na+ reabsorption?
Na+/glucose (SGLT1) and Na+/amino acid cotransport by secondary active transport
247
What is the main mechanisms of inter digestive period Na+ reabsorption?
Parallel Na+/H+ and CI-/HCO3- exchange in the ileum and proximal colon;
248
How can Cl- absorption occur and what drives it?
Can occur passively via transcellular or paracellular routes or through Cl-HCO3- exchange (ileum, proximal and distal colon) and parallel Na+-H+ and Cl-HCO3- exchange (ileum and proximal colon). It is driven by lumen negative potential caused by electrogenic transport of Na+
249
Where is Cl- secreted from?
Crypt cells
250
How does Cl- secretion occur?
Low intracellular Na+ drives inward movement of Na+, K+ and Cl- via NKCC1. K+ recycles via K+ channels, but intracellular concentration of Cl- increases providing an electrochemical gradient for Cl- to exit cell via CFTR on the apical membrane.
251
Why does little Cl- secretion normally occur?
Because the apical CFTR is either closed or not present (normally overshadowed by a higher rate of absorption)
252
What causes the CFTR to become abnormally activated, and what does this result in?
Indirect activators:
- Bacterial enterotoxins e.g. cholera or c. difficile
- Hormones and neurotransmitters e.g. VIP, 5HT
- Immune cell products e.g. prostaglandins
- Laxatives e.g. bile acids
- Second messengers e.g. cAMP etc
This results in secretory diarrhoea
253
What would the treatment of severe acuter diarrhoea involve?
* Maintenance of fluid and electrolyte balance (first priority)
* Use of anti-infective agents (if appropriate)
* Use of non-antimicrobial antidiarrhoeal agents (symptomatic)
254
What are the 4 main causes behind diarrhoea?
1) Impaired absorption of NaCl
2) Non-absorbable, or poorly absorbable, solutes in intestinal lumen (e.g. lactase deficiency) - "Osmotic Diarrhoea"
3) Hypermobility - "Hypermobility diarrhoea"
4) Excessive secretion - "Secretory diarrhoea"
5) increased capillary permeability due to inflammatory cells - "Inflammatory diarrhoea"
255
Which condition is a main example of secretory diarrhoea, and how does it work?
Cholera; and the toxin causes increased activity of adenylate cyclase which increase concentration of cAMP - which stimulates the CFTR to hyper secrete Cl-, with Na+ and water following
256
Which drugs can be used as anti-motility drugs in treatment of diarrhoea and why?
Opiate drugs e.g. codeine, diphenoxylate and loperamide; as they cause:
- inhibition of enteric neutrons
- Increased fluid absorption
- decreased peristalsis
- constriction fo sphincters
257
What are the functions of the liver?
- Metabolic processing
- Detoxification and degradation
- Synthesis of plasma proteins
- Storage
• Vitamins e.g. Vit B12, A and K
- Activation of vitamin D
- Removal of bacteria and old erythrocytes from the systemic circulation
- Secretion of hormones e.g. pepsin
- Production of acute phase proteins in infection
- Excretion of cholesterol and bilirubin
- Production of hepatic bile
258
In the liver, where do the arterioles of the hepatic artery, and the venues of the hepatic portal vein meet, and then go?
They meet in the sinusoids of the liver where they supply the lobules before draining into the central veins the liver lobule > branches of hepatic vein > hepatic vein
259
Blood and bile flow in opposite directions in the lobule - where does each go?
Blood > central vein in centre via sinusoids
| Bile > secreted by hepatocytes and flows outwards via cannaliculi to the 6 corners to be drained via bile duct of lobule
260
What are the hepatic plates?
Hepatocytes are arranged into hepatic cords (lines one cell thick) and 2 of these form to make the hepatic plates with the sinusoid between them
261
What is the Space of Disse?
aka perisinusoidal space - An extracellular gap between the hepatocytes and the endothelial cells that line the fenestrated sinusoids
262
What is found within the sinusoidal space of the liver?
* Endothelial cells as part of the fenestrated blood vessels
* Kipper cells - resident macrophages
* Stellate (Ito) cells within the space of Disse – important for storage of vitamin A
263
What is the intrahepatic bile system?
Excretion across apical membrane -> Canaliculi -> terminal bile ducts -> perilobular ducts -> interlobular ducts -> septal ducts -> lobar ducts -> R & L hepatic ducts -> common hepatic ducts
264
How much bile is produced continuously throughout the day?
0.6-1.2 litres per day
265
Where is bile produced from?
Hepatocytes (75%) and bile duct cells (cholangiocytes) (25%)
266
True or false: bile becomes more acidic when flow rate increases from the presence of chyme
False, bile becomes more alkaline when flow rate increases due to chyme, because chyme causes the release of secretin from S cells, which stimulates release of aqueous bicarbonate solutions
267
What is hepatic bile composed of?
- Primary bile salts (mainly chalice and chenodeoxycholic acid)
- Water and electrolytes
- Lipids and phospholipids
- Cholesterol
- IgA
- Billirubin
268
What are bile salts synthesised from?
Cholesterol (via 14 steps)
269
What happens in enterohepatic recycling?
Bile salts are reabsorbed from the SI at the terminal ileum (as fat digestion is normally complete by the terminal ileum) and is then returned to the liver where it is either:
a) re-circulated as a bile salt
b) broken down into cholesterol to be used as a substrate again for bile salt synthesis
270
Which influences cause the secretion of bile salts?
CCK, secretin, vagal activity, and bile salts retuning to the liver by recycling during and after a meal
271
What treatment can be used for non-pacified gallstones?
Ursodeoxycholic acid
272
Why can't morphine be used for biliary colic?
As it constricts the Sphincter of oddi, worsening the colic
273
What is the purpose of drug metabolism?
Convert parent drugs to more polar and, usually, less active metabolites that are not readily reabsorbed by the kidney, facilitating easier excretion
274
Which kinds of drugs aren't handled very well by the kidney and are readily reabsorbed and cause a long half life?
Highly lipophilic
275
What is the purpose of Stage 1 of drug metabolism?
Oxidation, reduction and hydrolysis - Makes the drug more polar, and adds a chemically reactive group ('handle') permitting conjugation
276
What is the purpose of Stage 2 of drug metabolism?
Conjugation - Adds an endogenous compound, increasing polarity for excretion
277
Cytochrome..
...P450 Family (CYP)
278
What is the main function of the cytochrome P450 family?
Cytochrome P450 mediate oxidation reactions (phase 1) of many lipid soluble drugs
279
What are 3 main gene families in the liver?
CYP1, CYP2, CYP3 (CP3A4 being the most important individual one)
