You Are What You Eat ALS Flashcards
1
Q
What is the area posterior to the liver, stomach and lesser omentum referred to as, and what is the only entry route to this called?
A
The lesser sac
The epiploic foramen (foramen of winslow) - a free edge of peritoneum
2
Q
Describe the quadrant location of the liver.
A
Majority is in the right upper quadrant and projects into the left upper quadrant
3
Q
What is the artery that supplies the spleen and what trunk does it originate from?
A
Splenic artery
Celiac trunk
4
Q
What is the embryonic derivative of the liver, gallbladder and pancreas, and what is the blood supply?
A
Embryonic foregut
Celiac artery
5
Q
What are the associated organs of the GIT?
A
Pancreas Liver Gallbladder Spleen Kidneys
6
Q
What other lipids besides TAG get taken into the intestine in our food?
A
Phospholipids (from cell membranes)
Cholesterol esters (from animal cell fat stores)
Cholesterol (from animal cell membranes)
7
Q
What is the structure of triacylglycerides (TAG)?
A
Glycerol backbone (3 carbons) with 3 fatty acids ester bonded (O-C=O) Fatty acid C=O and C+H Also possible to have monoglycerides and diglycerides
8
Q
What structures form from the embryonic foregut?
A
Oesophagus Stomach Proximal duodenum Liver Gall bladder Pancreas
9
Q
What is the efficiency of nutrient absorption in the gut?
A
Protein - 92%
Fat - 95%
Carbohydrate - 99%
Alcohol - 100%
10
Q
What enzymes are present in the mouth?
A
Amylase, lingual lipase
11
Q
What comprises the upper GIT?
A
Mouth, oesophagus, stomach and duodenum (liver, gallbladder and pancreas)
12
Q
What comprises the lower GIT?
A
Small intestine (jejunum and ileum) and the large intestine (caecum, vermiform appendix, ascending colon, transverse colon, descending colon, sigmoid colon, rectum, anal canal)
13
Q
What are the boundaries of the mouth? (Roof, floor, lateral walls, anterior, posterior)
A
Roof - Hard and soft palate Floor - Mylohyoid muscle Lateral Walls - Cheeks Anterior - Lips Posterior - Palatoglossal fold
14
Q
What are the contents and accessory glands of the mouth?
A
Vestibule and Oral Cavity
Teeth and Gums (gingivae)
Tongue
Salivary glands
15
Q
What are the 3 main salivary glands of the mouth? And what are their secretions?
A
Parotid (in the cheeks just anterior to the ears)
Submandibular (posterior to sublingual)
Sublingual (inferior to the tongue)
Secretion is serous (fluidy with enzymes), mucous (for lubricating bolus) or mixed
16
Q
What controls the secretion of saliva?
A
The parasympathetic and sympathetic branches of the autonomic nervous system. ANS regulates visceral functions.
Capsule - somatosensory fibres (somatic nervous system)
17
Q
Location of the parotid gland?
A
Inferior and anterior to the external auditory meatus
Lateral and posterior to the ramus of mandible
Anterior to the sternocleidomastoid muscle
Inferior to the zygomatic arch
18
Q
Describe the parotid duct.
A
~5cm long
Travels over the masseter muscle and through buccinator
Opening in the cheek to the vestibule of the mouth around the 2nd molar
19
Q
What illness can the parotid become inflamed during?
A
Mumps
20
Q
Describe to position of the submandibular gland.
A
Some of it is inferior to the mylohyoid muscle and some is on top in oral cavity
21
Q
Describe the submandibular duct.
A
Travels superior to the gland to empty in the sublingual papilla
22
Q
Describe the location of the sublingual gland.
A
Inferior to the tongue
Anterior to the submandibular gland
23
Q
Describe the sublingual duct.
A
Multiple ducts on an elevated crest on either side of the sublingual papilla
24
Q
Describe the role and features of the teeth.
A
To breakdown food
Up to 32 (28 plus wisdom teeth)
2 incisors, 1 canine, 2 premolars, up to 3 molars
25
Describe the nerve supply to the teeth.
Branches of the trigeminal nerve CN V (cranial nerve number 5)
Maxillary nerve V2 -> superior alveolar nerves
Mandibular nerve V3 -> inferior alveolar nerves (through mandibular foramen)
26
Describe the blood supply to the teeth.
Stems from the external carotid
Maxillary artery supplies both maxillary and mandibular teeth by different branches
Mandibular - inferior alveolar artery
Maxillary - posterior and anterior alveolar arteries
27
Where does the movement of mastication hinge?
Temporomandibular joint
Condyle of the temporomandibular joint hinges on the articular disc
Synovial joint
28
What are the main superficial muscles of mastication?
Temporalis - originates on the temporal line on the skull, fan shaped, has a fan shaped insertion on the coronoid process of the mandible
Masseter - originates along zygomatic arch, and inserts on the ramus of the mandible
Jaw closing (adductor) muscles
29
What is the nerve and blood supply to the superficial muscles of mastication?
Mandibular branch of the trigeminal nerve V3
| Maxillary artery and superficial temporal (corresponding veins)
30
What are the deep muscles of mastication?
Lateral pterygoid - from lateral side of lateral pterygoid plate, inserts on chondyle of mandible and articular disc, pulls mandible forward, opening, a lot of jaw opening is gravity but this helps
Medial pterygoid - associated with pharynx, from medial side of lateral pterygoid plate, similar orientation to masseter and function, closing
Attach to lateral pterygoid plate
31
What is the accessory muscle to mastication?
Buccinator - facial expression, prevents food from spilling into vestibule
32
What is the function of the extrinsic and intrinsic muscles of the tongue?
Intrinsic - form part of shape and used for vocalising, don't attach to bone
Extrinsic - move to move food around, attach to bone
33
What are the muscles of the tongue?
Genioglossus - attaches the genial spines of the mandible, helps protrusion of the tongue
Hyoglossus - attaches hyoid and then tongue, depresses tongue in contraction
Styloglossus - attaches styloid process then tongue, forms trough in middle of the tongue
Palatoglossus - Palate to tongue, forms palatoglossal fold, process of swallowing, keeps saliva in mouth, lifts up tongue pushing food into oropharynx
34
What are the nerve and blood supplies of the tongue?
```
Hypoglossal nerve (XII) except palatoglossus
Palatoglossus - Vagus nerve (X)
```
Primarily the lingual artery and veins
Secondary supply - tonsillar branch of facial artery and ascending pharyngeal artery
35
What is the general and special sensory innervation of the tongue?
General
Posterior 1/3rd - glossopharyngeal (IX)
Anterior 2/3rd - lingual nerve (mandibular division of trigeminal nerve V3)
Special
Posterior 1/3rd - glossopharyngeal (IX)
Anterior 2/3rd - facial nerve (VII) via chorda tympani
36
What stops food entering the nasopharynx during swallowing?
Levator veli palatini and musculus uvulae
| When they contract the passage is cut off
37
What forms the pharyngeal plexus?
Pharyngeal branches of the glossopharyngeal and vagus nerves
38
What are the 3 phases of swallowing?
Oral
Pharyngeal - Tongue, Soft palate, vocal folds, larynx and epiglottis, upper osophageal sphincter
Oesophageal
39
Describe the oesophagus.
```
Muscly tube - smooth muscle, persitaltic waves
~25cm
C6-T10
Sphincter at top and bottom
Oesophageal hiatus in diaphragm
```
40
Describe the upper oesophageal sphincter.
Skeletal muscle - possible to control
Cricopharyngeus and inferior constrictor muscles
Relaxes during swallowing
41
Describe the lower oesophageal sphincter.
Smooth muscle
Reinforced by right diaphragmatic crus
Prevents gastro-oesophageal reflux
42
Where are the anatomical constriction points of the oesophagus?
Pharyngo-oesophageal junction
Tracheal bifurcation - T5/T6
Gastro-oesophageal junction
43
What is the name of an image of the heart through the oesophagus?
Transoesophageal echocardiogram
44
What is the histology throughout the upper GIT?
Mouth, oropharynx, laryngopharynx and oesophagus - stratified squamous epithelium (not keratinised), good for abrasion, can become keratinised through heavy smoking
Stomach - simple columnar epithelium, parietal cells as well.
45
Where can you observe the difference in histology in the GIT?
Oesophago-gastric junction
With the simple columnar - only one layer so appears more red
With a lot of reflux cells will adapt and change so change from SSE to SCE
46
What is it called when the simple columnar epithelium migrate up into the oesophageal region?
Barrett's oesophagus - can be a precursor to oesophageal cancer
47
Describe the stomach.
Proximally fixed muscular bag
Length from incisors to gastro-oesophageal junction is 40cm
Size of stomach is variable when full
Food enters stomach through cardia
Fundus is top of the stomach
Greater curvature on left side
Lesser curvature on right side
Antrum is the bottom of the stomach
Pylorus leads to the pyloric sphincter and the duodenum
Lies in stomach bed
Peritoneal organ - completely covered by it
48
What is the blood supply to the stomach?
Coeliac trunk comes off of aorta
5 separate arteries:
Left and right gastric arteries, left and right gastroepiploic arteries, short gastric artery (which comes off the splenic)
49
What are the lymph nodes associated with the stomach?
Coeliac nodes by coeliac trunk of aorta
50
What is the innervation of the stomach?
Vagus nerve supplies the secretomotor which produces peristaltic and secretory action
Sympathetic nervous system - supplies visceral pain and vasculature
51
Describe the features seen on an endoscopy inside the stomach.
Rugae - ridges in the epithelium to help with the stretching of the stomach when food is in it
Also increases the surface area to aid with digestion - some are permanent some are not
52
Describe the muscles in the stomach that churns food.
Longitudinal and circular layers of muscle
53
What is food referred to once it reaches the stomach?
Chyme
54
Where does the chyme exit the stomach and where is this located on surface anatomy?
Pyloric sphincter into the duodenum and the transpyloric plane
55
Describe the duodenum.
25cm long
Peritoneal and retroperitoneal (behind the peritoneum)
4 parts - superior, descending, horizontal, ascending
56
What is in close association with the duodenum?
Gallbladder - lies anteriorly to the superior duodenum
| Pancreas - lies posteriorly to the curvature of the duodenum
57
Describe the superior duodenum (D1).
Peritoneal
Duodenal cap which is visible on radiological imaging (due to air)
Common bile duct and gastroduodenal artery are posterior
58
Describe the descending duodenum (D2).
Retroperitoneal (only front covered)
Receives common bile duct and pancreatic duct via hepatopancreatic ampulla (of Vater) at the major duodenal papilla
Where gastric acids are neutralised and other enzymes introduced
59
Describe the horizontal duodenum (D3).
Retroperitoneal
| Superior mesenteric artery and vein anterior, inferior vena cava and aorta posterior
60
Describe the ascending duodenum (D4).
Duodenojejunal flexure
| Ligament of Treitz - curves around the crus (diaphragm) and holds this part in place
61
What areas may appear dark on a barium swallow xray?
Fundus of the stomach
| Duodenal cap
62
What enzymes and digestive aids are in the stomach?
Pepsin, gastric acid, lipase
63
What enzymes are made in the pancreas?
Amylase, lipase, phospholipase, esterase
64
What are starches and sugars broken down into?
Monosaccharides
65
What are fats broken down into?
Free fatty acids and glycerol
66
What are proteins broken down into?
Amino acids
67
What is included in the concept of non-dietary loads?
```
Water (1200 ml/day)
Solids (800 g/day)
Saliva (1500 ml)
Gastric secretions (2000 ml)
Bile (500 ml)
Pancreatic secretions (1500 ml)
Intestinal secretions (1500 ml)
```
68
About how many litres of non-dietary fluid is removed by the digestive system per day?
8
69
What does salivary secretion include?
Water, ions, salivary amylase
70
What are the different cell types found in the stomach?
Mucous cells - secrete mucous to protect epithelium form acid secretions
Parietal cells - secrete HCl and intrinsic factor (for B12 absorption)
Chief cells - secrete pepsinogen (precursor to pepsin)
Enteroendocrine (APUD) - secrete protein hormones e.g. VIP and somatostatin
G cells (in pyloric antrum) - secrete gastrin
Stem cells - replace old mucosal and glandular epithelial cells
71
What are the phases of gastric secretion?
Cephalic - sight/smell/taste of food (vagus nerve)
Gastric - food in stomach (gastrin)
Intestinal - chyme in duodenum
72
What are the principle stimulants of acid secretion at the level of the parietal cell?
Histamine, gastrin and acetylcholine
73
How does histamine stimulate acid secretion at the level of the parietal cell?
Histamine is released from enterochromaffin-like (ECL) cells
Binds to H2 receptors on parietal cells
Activates adenylate cyclase (AC) and generates cAMP
74
How does gastrin stimulate acid secretion at the level of the parietal cell, both directly and indirectly?
Directly:
Released by G cells
Binds to CCK2 receptors that activate phospholipase C
Induces release of cytosolic calcium (Ca2+)
Indirectly:
Binds to CCK2 receptors on ECL cells to release histamine
75
How does acetylcholine stimulate acid secretion at the level of the parietal cell?
ACh is released from intramural neurons
| Binds to M3 receptors that are coupled to an increase in intracellular calcium (Ca2+)
76
How does an increase in intracellular cAMP and Ca2+ act in parietal cells?
Intracellular cAMP- and calcium-dependent signaling systems activate downstream protein kinases
This leads to fusion and activation of H+K+-ATPase, the proton pump
Pumps H+ out of parietal cells and K+ in
77
What is the difference between CCK receptors in the stomach vs the duodenum?
In the stomach CCK activation results in acid release
| In the duodenum CCK activation results in pancreatic secretion
78
How do CCK receptors recognise both CCK and Gastrin?
They have some amino acid sequences in common
79
What are the major hormones involved in the secretion and inhibition?
Gastrin - secreted by stomach in response to food especially protein, STIMULATES acid and pepsinogen secretion and gastric motility, INHIBITS gastric emptying
Secretin - secreted by the duodenum in response to acid, INHIBITS gastric acid production, INCREASES pancreatic and biliary bicarbonate secretion
CholeCystoKinin (CCK) - secreted by duodenum in response to food especially fat, INHIBITS gastric secretion and motility, STIMULATES pancreatic bicarbonate and enzyme secretion and bile secretion
Somatostatin - released from D-cells in stomach and duodenum in response to acid, INHIBITS gastric secretion
80
What mechanical process inhibits gastric secretion?
Stomach distension
81
What stimulates insulin secretion in response to glucose in the duodenum and what disease is it used to treat?
Glucose-dependent Insulinotropic Polypeptide
One of the 'Incretins' used to treat diabetes
Previously called Gastric Inhibitory Polypeptide (GIP)
82
What bacteria is responsible for excessive gastric acid secretion and how is this treated?
```
Helicobacter pylori - gram negative, produces urease to neutralise environment, causes gastritis
Antibiotics:
Amoxicillin + clarithromycin
Amoxicillin + metronidazole
Combined therapy
```
83
Describe the histology of the small intestine.
In the lumen wall consists of villi
Villi stick out and contain arteries veins and lymphatics
Crypts containing paneth cells at the bottom of villi
On the villi there is a brush border of microvilli
84
Describe the villi of the small intestine.
Each viilus is 0.5-1.5 mm long
20-40 villi/mm2
Total absorptive surface = 300 m2
On villi there are the mucus secreting goblet cells and absorptive enterocytes
85
Describe the movement of blood through the small intestine.
Arterial blood enters the villi and collects nutrients from the enterocytes
Venous drainage from the villi enters the hepatic portal vein
The liver controls entry of nutrients into the peripheral circulation
86
Describe the lymphatic drainage of the small intestine.
The lymphatic vessels of the small intestine are called lacteal
They extend into the villi and drain into the lymphatic system
This enters the circulation at the thoracic duct
The liver clears remnants after other tissues
87
Describe the function of crypts.
They contain paneth cells and stem cells
At the bottom of the crypt is the stem cell region, then up to the proliferative region, then the differentiated region
Between the proliferative and differentiated regions is the crypt-villus junction
Cell migration is from crypt to the top of the villus
88
What is the average life time of the small intestine mucosa?
```
~2-3 days
Damaged in coeliac disease and following anti-cancer drugs/radiotherapy leads to flattened mucosa and malabsorption
Renewed by cell proliferation in crypt
Migration from crypt to tip ~48h
Cells shed at tip of villus
```
89
What sense is in the mouth and what are the purposes of the enzymes in the mouth?
Taste
Salivary amylase - digestion of starch
Lingual lipase - digestion of triacylglycerol especially in neonates
Deactivated by acid in stomach
90
What is the function of gastric acid, enzymes and absorption in the stomach?
Gastric acid - protein denaturation
Pepsin - protein digestion
Gastric lipase - digestion of triacylglycerol
Absorption of alcohol, acidic drugs
91
How is the small intestine divided?
Duodenum - 1/6th
Jejunum - 1/3rd
Ileum - 1/2
92
What enzymes are secreted throughout the small intestine and what is absorbed in the different parts?
Duodenum:
Pancreatic amylase - digestion of starch
Lipase - digestion of triacylglycerol
Phospholipase - digestion of phospholipids
Trypsin, chymotrypsin, elastase - digestion of proteins
Dipeptidases (membrane bound and intracellular)
Disaccharidases (membrane bound)
Jejunum:
Continuing digestion, start of absorption
```
Ileum:
Continuing digestion
Absorption of -
Monosaccharides
Amino acids
Fatty acids, glycerol, other lipids
Many drugs
Water
```
93
What is the name of the inactive precursors of proteases?
Zymogens
94
What are the zymogens secreted and what activates them?
Pepsinogen -> pepsin - gastric acid, then pepsin
Trypsinogen -> trypsin - enteropeptidase
Chymotrypsinogen -> chymotrypsin - trypsin
Pro-elastase -> elastase - trypsin
Procarboxypeptidases -> carboxypeptidases - trypsin
Pro-aminopeptidases -> aminopeptidases - trypsin
95
What are the main end-products of salivary, gastric and pancreatic enzyme digestion?
Carbohydrate:
Disaccharides (maltose, sucrose, lactose)
Protein:
Short peptides, mainly dipeptides (60%)
Free amino acids (40%)
Fat:
Monoglycerides
Long chain free fatty acids
Glycerol
96
Describe the mechanism of disaccharide absorption.
Disaccharidases are membrane bound
Sucrase - sucrose -> fructose + glucose
Lactase - lactose -> glucose + galactose
Maltase - maltose -> glucose + glucose
Glucose active transport:
Glucose and galactose are transported with 2Na+ via a glucose transporter (SGLT) from the intestinal lumen into the mucosal cell
It is then transported into the blood via GLUT2 and the Na+ is pumped into the blood via Na+/K+-ATPase to maintain the concentration in the mucosal cell for further couple transport
97
How is the glucose active transport system used in disease?
Remains intact in diarrhoea/cholera and provides the scientific basis for oral rehydration supplements: NaCl: glucose: KCl
98
Summarise the breakdown and absorption of protein.
Protein is broken down by pepsin and pancreatic proteases to produce di- and tri-peptides, large peptides and free amino acids.
Large peptides - further digested by peptidases to form di- and tri-peptides or free amino acids
Di- and tri-peptides - transported into the cell via carriers
Some exist in small amounts
Some are further broken down to amino acids by cytoplasmic peptidases
Amino acids - transported into the cell via carriers
Luminal digestion:
40% free amino acids
60% peptides consisting primarily of 2-6 amino acid residues
99
How are end-products removed from small intestine?
Portal vein:
Carbohydrate - glucose, galactose, fructose, lactate
Protein - amino acids
Fat - short chain fatty acids (<12 carbons), glycerol
(short chain fatty acids: acetate (60%), propionate (20%) and butyrate (20%) are formed from fermentation of starch and dietary fibre in the colon)
Butyrate is thought to protect against colorectal cancer
Propionate may inhibit food intake
Lymphatics:
Fat - chylomicrons (>12 carbons)
100
Where does food pass through from the small intestine to the colon?
The ileocaecal valve
101
What are non-starch polysaccharides?
Dietary fibre:
Remains of plant cell walls, resistant to digestion
Includes (some) resistant starch and a variety of miscellaneous compounds
50% from vegetables
50% from cereals
UK recommended intake 18 g/d
102
What is the glycaemic index (GI)?
GI is the relative ability of carbohydrate food to increase blood glucose levels
Carbohydrates with a low GI value (55 or less) are more slowly digested, absorbed and metabolised
This causes a slower rise in blood glucose and, therefore insulin levels
103
What are the benefits of non-starch polysaccharides?
Absorb bile acids and cholesterol:
Increased clearance of cholesterol from the body
Bile acids may have tumour-promoting action
Absorb potential carcinogens in the colon
Increase viscosity of gut contents:
Slower absorption - may be beneficial in diabetes
Bacterial fermentation - mainly acetate, propionate and butyrate:
Butyrate may have anti-proliferate (anti-cancer) action
Propionate may have an anorectic effect (reduce food intake)
104
What non-invasive test can be used to see if there is a bacterial overgrowth in the colon?
The hydrogen breath test
| Spirometry looks at ppm of hydrogen in breath (from methane)
105
What is the efficiency of nutrient absorption in the gut?
Protein - 92%
Fat - 95%
Carbohydrate - 99%
Alcohol - 100%
106
Define pharmacokinetics.
Factors that determine the journey of the drug through the body
107
What does 'ADME' stand for?
Absorption, distribution, metabolism, and excretion - describes the disposition of a pharmaceutical compound within an organism
108
Describe absorption.
The mechanism of accumulation of a drug in a body compartment following administration.
109
Describe distribution.
The way in which a drug reaches each organ of the body.
110
What are xenobiotics?
A chemical compound foreign to a given biological system
111
What are the 4 main types of receptor?
Ligand-gated ion channels:
Membrane bound, ion channel effector, direct coupling, oligomeric assembly of subunits surrounding central pore
e.g. nicotinic acetylcholine receptor, GABAa receptor
G-protein coupled receptors:
Membrane bound, channel or enzyme effector, G-protein coupled, Monomeric or oligomeric assembly of subunits comprising 7 transmembrane helices with intracellular G-protein coupling domain
e.g muscarinic acetylcholine receptor, adrenoceptors
Receptor kinases:
Membrane bound, protein kinase effector, direct coupling, single transmembrane helix linking extracellular receptor domain to intracellular kinase domain
e.g. insulin, growth factors, cytokine receptors
Nuclear receptors:
Intracellular, gene transcription effector, coupling via DNA, monomeric structure with separate receptor- and DNA-binding domains
e.g. steroid receptors
112
Define pharmacodynamics.
The study of how a medicine acts on a living organism i.e. the study of a medicine's effect and the mechanisms of action.
113
What does pharmacokinetics influence?
The decided route of administration for a specific medication
The amount and frequency of each dose
114
What are the pharmacokinetic stages?
```
ADME
Absorption
Distribution
Metabolism
Excretion
(Measurement)
```
115
What is first pass metabolism?
When a drug goes through the liver and is metabolised first before distribution. Some of it is not available for therapeutic effect
116
What is first pass metabolism?
When a drug goes through the liver and is metabolised first before distribution. Some of it is not available for therapeutic effect
117
What are the routes of administration?
```
Oral or rectal
Percutaneous - Skin
Intravenous
Intramuscular
Intrathecal - CSF
Inhalation
(Placenta)
```
118
What are the routes of elimination?
Urine
Faeces
Milk, sweat
Expired air
119
In a pharmacokinetics graph (x - time, y - amount of drug in blood) what does the area under the curve signify?
Overall drug exposure
120
What is Cmax?
Highest concentration of drug in blood
121
What is t1/2 (half-life)?
Time at which drug has lost half its maximum concentration
122
What is Cmin?
Lowest concentration of drug in blood
123
What processes underly absorption in the body?
Multiple pathways (diffusion, carrier-mediated transport, and paracellular transport) contribute in parallel
Metabolism and efflux transport might be involved
Luminal solubility and stability affect apparent absorption
Regional differences in function exist along the length of the small intestine
124
What is the route of an oral medication and how can a drug be altered to absorb more in the intestines?
Dose
Disintegrate
Dissolved
Absorbed
You can coat a pill in an acid resistant coating, disintegrates more in GIT than stomach
125
What makes it harder to absorb a drug?
The stronger the acid/base nature of drugs, the harder it is to absorb them
126
How does slow absorption affect Cmax and duration of action?
It decreases Cmax but increases the duration of action
127
What is slow absorption from administration site into the plasma equivalent to?
A slow infusion at a variable rate
128
What does the rate constant Kabs govern and what does this assume?
Transfer of drug to central compartment
| Assumes that Kabs is directly proportional to amount of drug still unabsorbed
129
What happens to Cp once absorption is complete?
It declines with the same t1/2, irrespective of rate of absorption
130
What is Cp?
Concentration in plasma
| It is assumed to relate to extracellular fluid surrounding cells
131
What is the target concentration strategy?
Estimate initial dose (target dose, loading dose, maintenance dose)
Begin therapy
Assess therapy (patient response, drug level)
Refine dose estimate
Adjust Dose
Individual variation in response to drug is greater than Cp variation at that dose
This is routinely used in therapeutic drug monitoring (TDM)
132
What aspects of diet can modulate pharmacokinetics?
Grapefruit juice - can inhibit drug metabolism elevating levels in the body
Metal ions - can form complexes with drugs causing them to become insoluble
High fibre food - Absorbs secreted bile acid, bile acid helps to solubilise lipophilic drugs so this reduces their absorption
133
What drug may reduce absorption of local anaesthetics to general circulation?
Adrenaline
134
What can stop a drug moving between compartments?
It being bound, it must be free
135
What is the volume of distribution (Vd (mls))?
A theoretical volume that the total amount of administered drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it currently is in blood plasma.
Low if restricted to plasma water, lower dose required to achieve a given plasma concentration
High if can easily move out from plasma into other compartments
136
What is the absorption of drugs dependent on?
Formulation
Ionisation
Link to dose that can cause a relevant therapeutic response
137
Where can peptic ulcers form and how can pain be used to identify where they are?
Can form in the stomach or the digestive tract
The timing of pain is relevant to where it is - soon after eating is likely in the stomach whilst if 2-3 hours post eating it is likely to be in the small intestine
However they can be asymptomatic
138
What are the symptoms of peptic ulcers?
```
Pain in the abdomen/neck/navel/back (can last minutes to hours)
Bleeding
Indigestion/heartburn
Loss of appetite
Vomiting
```
139
What is the function of neck cells and where can you find them?
Produce mucous
| Cardiac, pylori and fundus
140
What is the function of chief cells and where can they be found?
Produce proteolytic enzymes (digestive)
| Fundus
141
What is the function of parietal/oxyntic cells and where are they found?
Produce HCl by pumping in protons
| Fundus
142
What enzyme in parietal cells produces protons?
Carbonic anhydrase
| CO2 + H2O -> HCO3 + H+
143
How does the parietal cell pump out H+ and HCO3-?
H+/K+-ATPase pumps K+ in and H+ into stomach
HCO3-/Cl+ pumps HCO3- into blood and Cl- into cell
Outflow of HCO3- into the blood increases blood pH leading to alkaline tide
144
What is the underlying mechanism causing peptic ulcers and what condition does it need to heal?
Disruption of stomach mucosal lining causes tissue damage by stomach acid
Caused by:
Bacterial infection e.g. H. pylori
Aspirin
To heal it needs a pH higher than 3
145
How does H. pylori cause a peptic ulcer?
Urease - produces NH3 + H2CO3
Induces gastritis
Disrupts stomach lining, stomach acid infiltrates, ulcer
146
How do proton pump inhibitors (PPIs) work?
Reduce H+ secretion by parietal cells
Prodrugs:
Enteric coating prevents rapid exposure to stomach HCl
However some use a bicarbonate coat to alter stomach pH and protect the PPI
Taken up by parietal cells:
At acidic pH conversion -> sulphenamides
Irreversible inhibition of H+ pump via ATPase
Short half-life 0.5-2 hours
Long lasting effect however due to:
Accumulation of the drug in parietal cell canaliculi
The irreversible nature of proton pump inhibition
147
How does H2 receptor antagonist reduce acid secretion?
Stops histamine binding to parietal cells
No cAMP produced in cell
Protons not pumped out
148
Why are PPIs used rather than H2 receptor antagonists?
Whilst H2 receptor antagonists are well tolerated generally PPIs have a better effect and safety profile
149
How can aspirin cause an ulcer?
NSAID - inhibits COX enzyme reduces levels of prostaglandins and thromboxanes in body
Prostaglandins:
Decrease gastric acid secretion
Increase mucous and HCO3- stomach secretion
Important in maintaining stomach lining - aspirin disrupts this
150
What can be given with NSAIDs to reduce possibility of an ulcer?
Prostaglandin mimetic such as Misoprostol
Decrease cAMP in parietal cells and decreases proton pump activity
151
What structures form from the embryonic midgut?
```
Distal duodenum
Jejunum
Ileum
Caecum
Vermiform appendix
Ascending colon
Proximal 2/3 transverse colon
```
152
What structures form from the embryonic hindgut?
```
Distal 1/3 transverse colon
Descending colon
Sigmoid colon
Rectum
Proximal anal canal
```
153
What artery supplies the embryonic foregut?
Coeliac artery
154
What artery supplies the embryonic midgut?
Superior mesenteric artery
155
What artery supplies the embryonic hindgut?
Inferior mesenteric artery
156
What layers are there of the anterolateral abdominal wall, superficially to deep?
```
Skin
Superficial fascia - fatty layer (Camper's fascia)
Superficial fascia - membranous layer (Scarpa's fascia)
External oblique muscle
Internal oblique muscle
Transverse abdominus muscle
Transversalis fascia
Extraperitoneal fascia
Parietal peritoneum
```
157
What muscle cover the anterior abdominal wall, and what is a key feature of it??
Rectus abdominus
| Has tendinous intersections which form the 'six pack'
158
What is the name of the aponeurotic ends of the anterolateral muscles which covers the rectus abdominus?
Rectus sheath
159
Describe the external oblique.
Wide origin: 8 digitations from inferior 8 ribs
Inferomedial fibre orientation (look like they point down)
Insertion: linea alba, iliac crest, pubic tubercle
Aponeurotic anterior, medial to tip of 9th costal cartilage (rectus sheath)
Aponeurosis forms inguinal ligament (Anterior Superior Iliac Spine - Pubic Tubercle (ASIS-PT))
160
Describe the internal oblique.
Wide origin: lumbar fascia, iliac crest and lateral 2/3 inguinal ligament
Superomedial fibre orientation (looks like its pointing upwards)
Insertion: linea alba, pecten pubis and ribs 10-12
Aponeurotic anterior, medial to tip of 9th costal cartilage (rectus sheath)
Forms part of the conjoint tendon
161
Describe the transversus abdominus.
Wide origin: lumbar fascia, iliac crest, costal cartilages 7-12 and lateral 1/3 inguinal ligament
Transverse fibre orientation (side to side)
Insertion: xiphisterium, linea alba, pubic crest
Aponeurotic anterior, medial to tip of 9th costal cartilage (rectus sheath)
Forms part of the conjoint tendon
162
Describe the rectus abdominus.
Origin: crest of pubis and pubic symphysis
Insertion: costal cartilage 5-9, xiphisternum
3 tendinous insertions
163
How are the aponeuroses of the 3 anterolateral muscles organised superior and inferior to the arcuate line?
Superior:
The external oblique passes anteriorly to the rectus abdominus
The internal oblique surrounds the rectus abdominus
The transversus abdominus passes posteriorly
Inferior:
All 3 pass anteriorly
The horizontal arcuate line (1/2 distance from umbilicus to pubic crest) demarcates lower limit of the posterior layer of the rectus sheath
Transversalis fascia and parietal peritoneum are always posterior
164
What are the boundaries of the inguinal canal?
The floor - inguinal ligament and thickened medially by the lacunar ligament
The anterior wall - aponeurosis of external oblique, and internal oblique laterally
The roof - internal oblique, transversus abdominus, and transversalis fascia
The posterior wall - transversalis fascia
The anterior wall contains the superficial inguinal ring
The posterior wall contains the deep inguinal ring
165
What passes through the inguinal canal?
Males:
Spermatic cord
Genital branch of the genitofemoral nerve
Ilioinguinal nerve
Females:
Round ligament
Genital branch of the genitofemoral nerve
Ilioinguinal nerve
166
What complication can you have due to the inguinal canal being a 'weak point' in the abdominal wall?
Inguinal hernia
167
What are the functions of the abdominal muscles?
Moves the trunk
Supports intestines
Depress the ribs
Increases intra-abdominal pressure (during Valsalva manoeuvre (bearing down to pass faeces))
168
What is the parietal peritoneum?
Serous membrane that lines the abdominal wall
169
What is the visceral peritoneum?
Serous membrane lines the abdominal viscera
170
What is the peritoneal cavity?
Potential space
171
What is mesentary?
Double fold of peritoneum attaches intestines to wall
172
What is omentum?
Fold of peritoneum connecting the stomach with other abdominal organs
Greater omentum drapes over the intestines
Lesser omentum superior to stomach connects it to liver
173
What are the muscles of the posterior abdominal wall?
Quadratus lumborum
Psoas major
Iliacus
174
What separates the duodenum and the jejunum?
Duodenojejunal junction
175
What is the histology of the small intestine?
Simple columnar epithelium
176
Describe the jejunum.
```
Proximal 2/5 of the small intestines
Thicker wall
Larger calibre >3cm
Prominent plicae circularis (folds in lumen to increase absorption)
Long vasa recta (vessels from arterial arcades in mesentery)
Less fat in mesentery than ileum
Primary site for absorption (majority)
Umbilical and left regions
```
177
Describe the ileum.
```
Distal 3/5
Thinner wall
Smaller calibre <3cm
Increase Peyer's patches (lymphoid nodules) - detects how much bacteria in system
Short vasa recta
Increase arcades, more fat
More B12, bile salts, H2O and lipid absorption
Hypogastric and right inguinal regions
```
178
What is found in ~2% of the population?
Meckel's diverticulum:
A slight bulge in the small intestine present at birth
Vestigial remnant of the vitelline duct ( from opening to yolk sac in embryo)
~2 inches in length
Near to ileocaecal junction
179
Describe the large intestine.
5 feet long
Absorbs H2O, electrolytes and drugs and stores waste
Part retroperitoneal
2 flexures
180
What arteries supply the colon with blood?
Superior mesenteric artery:
Caecum, vermiform appendix, ascending colon, proximal 2/3 transverse colon
Inferior mesenteric artery:
Distal 1/3 transverse colon, descending colon, sigmoid colon, rectum, proximal anal canal
181
What arteries branch off of the superior mesenteric artery?
Ileocolic artery - caecum, 1/3 ascending colon
Right colic artery - 1/3 ascending colon
Middle colic artery - Hepatic flexure
Marginal artery - Transverse colon and splenic flexure
182
What are the two flexures of the colon?
Right colic flexure - hepatic flexure
| Left colic flexure - splenic flexure
183
Describe the location of different parts on the colon in respect to the peritoneum?
```
Intraperitoneal: (have mesentery - flexible so could be ostomied)
Appendix
Caecum
Transverse colon
Sigmoid colon
```
Retroperitoneal:
Ascending colon
Descending colon
184
What are distinguishing features of the colon?
Taeniae coli - muscular strands that contract to move faecal matter along the large intestine (line in middle of tube)
Haustra - bulges that help to shape large intestine
Appendices epiploicae - deposits of fat
185
Describe the vermiform appendix.
Cul-de-sac 6-9cm
Variable position - retrocaecal/retroileal
Mesoappendix - Portion connected to mesentery
Appendicular artery from posterior caecal
Taeniae coli fuse at base
Opens into posteromedial caecum, 2cm inferior to ileocaecal valve
Unclear function
186
What are the symptoms of appendicitis?
Referred pain to umbilicus region due to visceral innervation of midgut
Then localise pain caused by involvement of parietal peritoneum as inflammation progresses
187
What are the functions of the hindgut in regards to faeces?
Descending colon:
Storage point
Sigmoid colon:
Stool completes solidification - H2O has been absorbed
Moves stools into rectum
Rectum:
Holding area for faecal matter
188
Describe the rectum.
S3 - pelvic floor (15cm)
Ends at anorectal junction
Rectal ampulla houses faecal matter
No appendices epiploicae
No haustrations
Taeniae fuse
Transverse rectal folds for faeces to sit on top of
Peritoneum - Prox 1/3 - ant and bilateral
- Mid 1/3 - ant
- Dist 1/3 - nil (infraperitoneal)
189
Describe the anal canal.
Tube in a funnel
Last 4 cam of GIT
Circular muscles
Pectinate line (dentate line) - difference in embryological origin (ectoderm), non-keratinised stratified squamous epithelium
Anocutaneous line - below this point epithelium is keratinised where anal verge becomes continuous with perianal skin
Internal anal sphincter - smooth muscle the runs alongside rectum then anal canal
External anal sphincter - skeletal muscle, lateral to internal sphincter, deep, superficial and subcutaneous
190
What is the blood supply to the rectum and anal canal?
Branches of the inferior mesenteric and internal iliac:
Superior rectal artery and vein - rectum
Inferior rectal artery and vein - anal canal
Venous complex of anal canal can varicose due to straining/constipation
This causes haemorrhoids
Superior to pectinate line - internal haemorrhoid
Inferior to pectinate line - external haemorrhoid
191
What is the nerve supply to the rectum and anal canal?
Smooth muscle of rectum and anal canal (internal anal sphincter):
Parasympathetic nerves from S2, S3 and S4 (pelvic splanchnic nerve)
Sympathetic nerves from T11-L2 (inferior hypogastric plexus)
Visceral sensory fibres follow the parasympathetic supply
External anal sphincter:
Inferior anal nerve (somatic motor and sensory) pudendal nerve or sacral plexus
192
What are the innervative steps of defecation?
Faeces stretch the rectum and stimulate stretch receptors, which transmit signals to the spinal cord
A spinal reflex stimulates contraction of the rectum
The spinal reflex also relaxes the internal anal sphincter
Impulses from the brain prevent untimely defecation by keeping the external anal sphincter contracted
Defecation occurs only if this sphincter also relaxes, needs voluntary relaxation of external sphincter for defecation
Valsalva manoeuvre
193
Why is it an issue that fats (mainly TAG) are immiscible in water?
They have to be digested in an aqueous environment, the intestine
- they are emulsified into small droplets (1-100 μm) and their stabilisation by bile salts and amphipathic lipids for enzyme action
They have to be transported around the body in the blood, also an aqueous environment
- coat TAG-rich particles with protective proteins and amphipathic lipids
194
What are the basics of fat digestion?
Emulsification in the mouth and stomach at 37°C liquifies and emulsifies the bulk lipid phase into small (1-100 μm) droplets. Increases the surface area of TAG droplets for enzyme attack
Bile salts from gallbladder and amphipathic lipids coat small emulsion particles preventing the re-aggregating into bulk TAG phase (duodenum)
Lipases degrade TAG
Bile salts solubilise products of lipase digestion into micelles (nm size) to facilitate uptake into enterocytes in jejunum region
195
What is the enzymatic action on phospholipids, TAG and cholesterol esters in the duodenum/jejunum?
Phospholipids -> free fatty acids + lisolipids - phospholipase A
Cholesterol esters -> free fatty acids + cholesterol - cholesterol ester hydrolase
TAG droplet -> 2 monoglycerides + free fatty acids - pancreatic lipase and colipase
All of these enzymes are secreted by the pancreas, although colipase is secreted as procolipase
196
What are the actions of pancreatic lipase, bile salts and colipase in fat digestion?
Pancreatic lipase hydrolyses long chain triglycerides from fat droplet
Bile salts coat lipid droplet, stabilise and prevent association with lipase
Addition of colipase prevents association of lipase with the bile salt-coated fat droplet
Plateau of fatty acid release when bile salts are added, released again once colipase is added
197
What are the sources of lipid-degrading enzymes?
Lingual lipase - Ebner's glands on dorsal surface of tongue, activity continued in stomach
Gastric lipase - cleaves 15-20% of dietary TAG fatty acids, especially important in neonate for milk TAG digestion, churning action of stomach at 37°C emulsifies bulk TAG phase (VERY IMPORTANT)
Pancreatic triglyceride lipase, bile salt-activated lipase, pancreatic lipase related protein 2, phospholipases, cholesterol esterases - all produced in pancreas
198
How much fat may we ingest in a day and what % of our total dietary energy intake is this?
100-150g
| 40% or more
199
Where does fat come from in our diet?
```
Milk and milk products
Cheese
Cream
Butter
Margarines
Cooking oils
Lard
Meat fats
Eggs
Cereal grains
Nuts
Fat-rich fish
Fruit (e.g avocado)
```
200
What vitamins are taken in with fat?
```
Fat-soluble vitamins
A
D
E
K
Essential w-6 and w-3 fatty acids - linoleic acid, linolenic acid, respectively
-essential as they cannot be synthesised
```
201
What is the significance of emulsification and how are droplets prevented from re-aggregating?
The churning action of the stomach at 37°C emulsifies the bulk TAG phase into small droplets 1-100 microns or less in diameter, these have a much larger surface area for lipase enzymes to act on
In duodenum, particles become coated with bile salts and more amphipathic phospholipids and cholesterol, the more polar surface prevents small emulsion droplets from re-aggregating yet allows lipase action to degrade the TAG
202
What are the steps of lipid absorption?
Breakdown of products of lipid digestion + amphipathic bile salts = micelles
Micelles travel to apical brush border of intestinal epithelial cells (ECs) and release products for digestion
Once inside intestinal ECs lipid products are re-esterified with FFA = PLs, CEs, TAGs
Re-esterified lipids + apo(lipo)proteins = chylomicrons
Chylomicrons migrate to basolateral membrane of the ECs of the small intestine and exocytosis occurs into the lacteals, the thoracic duct and ultimately the blood
Bile salts are recirculated from the ileum to the liver via the enterohepatic circulation
203
Why may alcohol abuse lead to greasy, diarrhoeal bowel movements?
Excessive alcohol consumption is the most common cause of chronic pancreatitis and a very frequent cause of pancreatic insufficiency
Patients who suffer from chronic pancreatitis produce insufficient amounts of lipase which is crucial for the digestion of lipids
Malabsorption of lipids results in the excretion of greasy stools or steatorrhea
204
What is the composition of bile?
Bile is continuously formed by the liver and secreted to the gallbladder where it is stored and concentrated
```
Water - 97%
Bile salts - 0.7%
Bile pigments - 0.2%
Cholesterol - 0.06%
Inorganic salts - 0.7%
Fatty acids - 0.15%
Phospholipid (lecithin) - 0.1%
Fat - 0.1%
Alkaline phosphatase - ...%
```
205
What is the comparison of contents between the hepatic duct bile and gallbladder bile?
Hepatic duct bile:
Percentage of solids - 2-4
Bile salts (mmol/L) - 10-20
pH - 7.8-8.6
Gallbladder bile:
Percentage of solids - 10-12
Bile salts (mmol/L) - 50-200
pH - 7.0-7.4
More concentrated in gallbladder bile
206
What are the breakdown products of cholesterol?
Bile acids
They are conjugated to glycine and taurine making one end more polar and are present in bile as the Na and K salts
They are powerful detergents - deoxycholic acid, lithocholic acid e.g.
207
Where are primary and secondary bile acids made?
Primary bile acids are made by the liver - cholic acid, chenodeoxycholic acids
Cholic (from cholyl-CoA) - taurocholic acid, glycocholic acid
Chenodeoxycholic (from chenodeoxycholyl-CoA) - taurochenodeoxycholyl acid, glycochenodeoxycholyl acid
Secondary bile acids are formed by bacterial action in the intestine
Deoxycholic acid - from glycocholic acid
Lithocolic acid - from tauro- and glycochenodeoxycholyl acid
208
Describe the structure of bile acids.
Bile acids have a planar structure with all polar groups on one face and non-polar groups on the other face
Amphipathic
Aggregate in nm size micelles and are good detergents
209
How are bile acids circulated?
There is an enterohepatic circulation of bile acids with some being lost each day in the faeces
In this way some cholesterol is excreted daily (only way it can be excreted)
210
What stimulates bile acid to be secreted?
Cholecystokinin (CCK)
Released from the duodenal mucosa when food enters the intestine
CCK in blood stimulates the gallbladder and relaxation of the sphincter of Oddi
This is normally closed to prevent bile and hepatic secretions flowing into the intestine until required
211
Describe gallstones, the different terms associated with them and risk factors.
Cholelithiasis - stones in the gallbladder
Choledocholithiasis - stones in ducts of the biliary tree
Cholesterol stones - 70-80% cholesterol
Pigment stones - bile pigments (bilirubin, biliverdin)
Mixed stones
Risk factors:
- Caucasian
- Females
- Low fibre
- High cholesterol
- Starchy diet
- Overweight
```
5 F's:
Fair
Fat
Female
Forty
Fertile
```
212
How is the digestion of TAG and phospholipids incomplete?
Most TAG is degraded to 2-monoacylglycerol with only a little glycerol being formed depending on how long the food remains in the duodenum
The reaction of TAG -> DAG is fast and DAG -> 2-MAG is fast but the reaction of 2-MAG -> Glycerol is slow
213
What do micelles of bile salts solubilise?
Fatty acids
2-MAG
Lysolipids (from PLs and C)
3-10nm diameter
Transport lipid digestion products to the microvilli of enterocytes
214
What is the purpose of the unstirred water layer at the enterocyte surface?
Directs micelles to the enterocytes
Without bile salts fatty acids and 2-MAG are absorbed much more slowly
Bile salt micelles deliver products of fat digestion across an unstirred water layer to the enterocyte membrane
Here they are taken up by carrier-mediated and/or passive diffusion mechanisms
215
What happens to bile salts after helping transport lipid digestion products?
Bile salts are not absorbed
| They are transported to the ileum for reabsorption and recycling
216
What happens in the enterocytes following absorption of lipid digestion products?
Fatty acids and 2-MAG are reassembled into TAG
Some protein is added and the TAG is secreted as chylomicrons
Chylomicrons are 75-1000nm in diameter (too big for capillaries)
This occurs as the TAG droplet passes from the endoplasmic reticulum to the Golgi where glycosylation of proteins occurs
Cholesterol, cholesterol ester and fat-soluble vitamins are added to the chylomicrons which move in vesicles to the plasma membrane via exocytosis
These are secreted into lacteals (lymphatic vessels) and enter circulation via the thoracic lymph duct
Blocking protein synthesis stops chylomicron release so TAG accumulates in the enterocytes
Glycerol and short chain fatty acids (C4-10) are water-soluble and pass through enterocytes directly into the blood
217
What is the structure of circulating chylomicrons and very low density lipoproteins (VLDLs)?
Very similar structure between chylomicrons, VLDLs and low density lipoproteins (LDLs):
- Mainly amphipathic lipid monolayer with free cholesterol within
- Core of mainly non-polar lipids e.g cholesteryl ester and TAG
Difference between them in surface apoproteins on particle surfaces:
- Peripheral apoprotein - e.g. apo C
- Integral apoprotein - e.g apo B
High density lipoproteins (HDLs) have a disc-like shape initially and are the smallest with the lowest % of TAG
Chylomicrons transport dietary fat from intestine to tissues via plasma and have the highest % of TAG and are the largest
Other lipoproteins circulate fat between tissues in the plasma
218
What are the main apoproteins and their suggested functions?
```
A1 - Activates lecithin-cholesterol acyltransferase (LCAT)
A2 - Inhibits LCAT?, activates hepatic lipase
B-48 - Cholesterol clearance
B-100 - Cholesterol clearance
C1 - Activates LCAT?
C2 - Activates lipoprotein lipase (LPL)
C3 - Inhibits LPL?, Activates LCAT?
E - Cholesterol clearance
```
219
What is the metabolism of chylomicrons?
After ingesting a fatty meal the plasma goes opaque with chylomicrons but clears again in one to two hours as chylomicrons are metabolised
They are broken down by lipoprotein lipase on capillary surfaces
220
What is the importance of omega-3 (w-3) and omega-6 (w-6) fatty acids?
Omega-3:
- Anti-inflammatory
- Polyunsaturated fatty acids
- Role in the body: control blood clotting, build cell membranes in the brain, normal growth and development
- Research indicates role in blood pressure, rheumatoid arthritis, and depression
Omega-6:
- Pro-inflammatory
- Polyunsaturated fatty acids
- Role in the body: brain function, normal growth and development
221
What kind of fat may reduce metabolic disease and are promising therapeutic targets?
Brown fat
222
What are the associated organs of the GIT?
```
Pancreas
liver
Gallbladder
Spleen
Kidneys
```
223
What are the associated organs of the GIT?
```
Pancreas
Liver
Gallbladder
Spleen
Kidneys
```
224
What are the functions of the liver?
```
Regulation of glycogen storage
Decomposition of red blood cells
Plasma protein synthesis
Hormone production
Detoxification
Production of bile - accessory digestive gland
```
