Systems 2 - Gastrointestinal Flashcards
Functions of the GI tract
DIGESTION - process by which food and large molecules are chemically degraded to produce smaller molecules.
ABSORPTION - process by which nutrient molecules are absorbed by cells that live in the GI tract, and enter the blood stream.
Layered structure of GI tract
Same overall structure throughout, but some regional variation.
Serosa Longitudinal muscle - Muscularis externa MYENTERIC PLEXUS Circular muscle - Muscularis externa SUBMUCOSAL PLEXUS (only small + large intestines) Submucosa Muscularis mucosae - Lamina propria - Mucosa Epithelium -
Amplification of surface area in GI tract
- Folds of kerching / pilacae circulares - gross folds in small intestine, moved by muscularis mucosae
- Villi and crypts
- Microvilli on villus columnar epithelial cells - covered in network of glycocalyx to create unstirred layer essential for absorption of fat
Crypt - positioning of cells
TOP
Absorptive cell (goblet cells interspersed)
Microvacuolated columnar cell
Stem / progenitor cell (can turn over whole cell population in 2 weeks)
Enteric endocrine cell
BOTTOM
Absorptive cell
Basolateral membrane:
Na/K ATPase (Na⁺ out, K⁺ in)
Na/Cl cotransporter (Na⁺ and K⁺ in, Cl⁻ in)
K⁺ channel (K⁺ out)
Apical membrane:
Cl⁻ out into lumen
Na⁺ and H₂O move paracellularly into lumen, following Cl⁻
Gastrointestinal secretions
From salivary glands, gastric glands, exocrine pancreas, liver-biliary system, intestine.
8-9L/day
Contains - enzymes, ions, water, mucus
Function - breakdown large compounds, regulate pH, duilute, protect
Blood circulation of GI tract
Splanchnic circulation directs blood leaving small intestine to liver for processing, before entering IVC
Progressive activation following a meal, stomach first
Microvasculature of villus
Arteriole
Venule - amino acids and sugars leave here
Central lacteal - fats broken down, resynthesised and transported out here
Regulatory mechanisms to control GI function
ENDOCRINE - release of transmitter into blood for delivery to distant target cell
PARACRINE - release of transmitter from sensor cell to adjacent target cell without entering blood or activating neurones (local regulation)
NEURONAL
GI hormones
Gastrin - regulates gastric secretion and motility
Cholecystokinin (CCK) - gallbladder contraction and pancreatic secretion
Somatostatin - inhibits gastric secretion
Enteric nervous system
Postganglionic parasympathetic neurones
100 million neurones in (same as in spinal chord)
Myenteric plexus and submucosal plexus are complete self-sustaining networks of neurones
Transmitters in intrinsic and extrinsic NS
Intrinsic NS can self-regulate, Extrinsic NS enhances long term.
Intrinsic NS - acetylcholine and substance P are excitatory
- vasoactive intestinal peptide and nitric oxide are inhibitory
Extrinsic NS - acetylcholine for parasympathetic
- noradrenaline for sympathetic
Mechanisms for stimulating acid secretion
Hormonal regulation Neuronal regulation (before food even in stomach)
Multiple mechanisms
- > redundancy
- > precise control
Phases of GI control
Cephalic (sight, smell, taste, chewing)
Gastric (distension of stomach wall, acidity)
Intestinal (distension of SI wall, acidity, osmolarity)
Non-propulsive movement / segmentation
Rhythmic contraction and relaxation of circular muscle
Mixes chyme and brings all into contact with mucosal surface
Peristalsis
Relatively infrequent
Progressive contraction of successive sections of circular muscle
Propels chyme a short distance, allowing time for digestion and absorption
Reservoir function of GI tract
Lower oesophageal sphincter and pyloric sphincter allow stomach to act as reservoir
Tonic, long lasting contractions allow stomach to hold and process food-stuffs
Length of time depends on contents, longest hold for proteins and fats
GI smooth muscle cells
Small
Muscle fibres act together as a single functional unit, gap junctions for coordinated contraction
Contraction of GI smooth muscle cells regulated by calcium
Calmodulin + calcium
+ myosin light chain kinase
+ ATP + myosin with nonphosphorylated light chain
-> activated proteins
Raised intracellular calcium -> contraction
Mechanisms of Ca²⁺ release
Voltage-independent Ca²⁺ channel (Ca²⁺ induced Ca²⁺ release to ryanodine receptor)
Voltage-gated Ca²⁺ channel (Ca²⁺ induced Ca²⁺ release to ryanodine receptor)
G protein receptor -> intracellular signal via IP3-gated Ca²⁺ channel
Smooth muscle action potentials
Slow waves over seconds, not ms
Depolarised resting membrane potential
Oscillating membrane potential
Low amplitude (5-15mV)
Variable frequency (3-12/min), slowest in stomach, fastest in SI
Modulated by hormones, intrinsic/extrinsic nerves, body temp, metabolic activity
Fasted vs fed state affect on smooth muscle action potentials
Fasted - migrating motor complex
- periods of none, then bursts of muscular activity
- needed to clean GI tract to prepare for next meal
Fed - segmentation and peristalsis
- continuous low level activity
Sphincters
Specialised circular muscles separate two adjacent components of GI tract
Maintains positive resting pressure
Regulate forward and reverse movement
Regulation coordinated with smooth muscle contractions of adjacent compartments
One way valves, only open for pressure on proximal end
Salivary secretion
Parotid gland - largest salivary gland, serous secretion rich in α-amylase
Submandibular and sublingual glands - seromucous secretion
Minor glands scattered throughout oral cavity - muscous secretion rich in mucin glycoproteins
Saliva
1.5 L/day
Hyposmotic (lower osmolarity than plasma)
pH around 7
MUCIN GLYCOPROTEINS to lubricate food
LYSOZYME and PROLINE-RICH PROTEINS to clean and protect the mouth cavity
α-AMYLASE to reduce starch to oligosaccharide molecules
LIPASE (small amount) for fat digestion
Salivary gland structure
Gland - interlobular duct - Lobule - intercalated duct - Acinus - each produces one product Acinar (make zymogen granules, packets of produced proteins) and duct epithelial cells
Acinar cells at end of duct, where product is made. Leaky, salt and water can pass between
Duct lining cells along duct, tight junctions
Secretion is modified along duct, add HCO₃⁻ and K⁺, remove Na⁺ and Cl⁻
Acinar cells secretion
1- inwardly directed Na⁺ gradient across basolateral membrane
2- Cl⁻ accumulates intracellularly, driven by Na⁺ gradient
3- K⁺ ions out, maintain driving force for Cl⁻ exit across apical membrane
4- Cl⁻ exits cell into duct via channels
5- draws Na⁺ and water through paracellularly, so secretion of NaCl
ACh and CCK potently stimulates NaCl secretion by acinar cells
Regulation of saliva secretion
Parasympathetic - stronger and more long lasting stimulation
- esp. synthesis and secretion of salivary amylase
Sympathetic - transient stimulatory effect
NO HORMONAL CONTROL
Vomiting - why?
Beneficial for survival, to rid animal of toxins
Controlled by brain stem, stimulated by by neural and hormonal factors
Coupled with nausea to condition avoidance of future toxin ingestion
Or induced by higher centres
Vomiting sequence
Reverse peristalsis:
- > soft palate and glottis close (stop respiration)
- > pyloric sphincter, LES and stomach relax
- > forced inspiration against a closed glottis, diaphragm and abdominal muscles contract
- > increased intra abdominal pressure, contraction of stomach
- > reflex relaxation of upper oesophageal sphincter
Embryology - week 3
Gastrulation to become:
Ectoderm (-> nervous system, epithelium of skin)
Mesoderm (-> connective tissues- blood, bone, muscle, GI and respiratory tract connectives)
Endoderm (-> GI tract organs and epithelium of GI and respiratory tract)
Week 4-5
Primitive gut tube formed, distinguishable sections to pharyngeal, fore, mid, hind gut.
Mesenteries formed - from mesoderm
- foregut structures attached at front and back to ventral and dorsal mesogastrum
- liver develops in ventral mesogastrum, spleen in dorsal, lesser sac forms between them
- greater omentum grows down in front, 4 cell layers fusing
Foregut supply
Mouth-first 1/3 (descending) duodenum Coeliac trunk Coeliac ganglion (sympathetic) Vagus nerve (parasympathetic)
Midgut supply
2/3 duodenum-2/3 transverse colon
Superior mesenteric artery
Superior mesenteric ganglion (sympathetic)
Vagus nerve (parasympathetic)
Hindgut supply
Last 1/3 transverse colon-anus
Inferior mesenteric artery
Inferior mesenteric ganglion (sympathetic)
Splanchnic nerve (parasympathetic)
Development of mouth
Initially stomadeum
Oropharyngeal membrane ruptures at 4 weeks (miscarry if not)
Development of pharyngeal arches and pouches
Externally - 5 arches with 4 clefts between, forming the muscles and skeleton of face
Internally - 4 pouches from outpouching of foregut
I - auditory tube and middle ear cavity
II - palatine tube
III - inferior parathyroid gland and thymus
IV - superior parathyroid gland and parafollicular cells of thyroid
III and IV will swap position as embryo curls
Development of tongue, and associated nerves
Develops from pharyngeal arches
Anterior 2/3 - sensation from trigeminal, taste from facial
Posterior 1/3 - taste and sensation from glossopharyngeal
All motor sensation from hypoglossal
Development of stomach
Week 4 starts to dilate
Dorsal wall grows faster than ventral, creating greater and lesser curvatures
Rotates longitudinally and anterioposteriorly, dorsal and ventral mesenteries twist in process
Development of duodenum
Pushed onto dorsal wall, so 1st part of duodenum remains intraperitoneal and 2nd part is retroperitoneal as membrane at back fuses and is reabsorbed
To form C shaped loop on right of cavity
Development of liver and gallbladder
Outgrowth of endoderm in week 3
Liver bud grows against septum tranversum (which will become diaphragm)
Main haematopoeitic organ from week 10-month 7
Cystic diverticulum off duodenum becomes ballbladder
Bile production begins week 12
Development of pancreas
2 buds - dorsal and ventral
Ventral bud migrates with bile duct behind duodenum and fuses to dorsal bud
Duct systems fuse, forming the main pancreatic duct
Development of spleen
NOT derived from endoderm tube
At week 5, proliferation of mesoderm in dorsal mesogastrum
Rotates, moves to left, stays intraperitoneal
Haematopoietic and lymphoid function
Midgut formation
Primary intestinal loop - formed in week 5 as midgut elongates. Attached to yolk sac by vitelline duct.
At weeks 6-10, loop elongates, coils and twists to mature position
Problems in midgut formation
Meckel’s diverticulum - retained connection between midgut and yolk sac, appendicitis-like symptoms
Abnormal gut rotation - risk of twisting mesentery and occluding blood supply
Omphalocele - where midgut doesn’t return to abdomen, organs remain in sac outside (usually many other defects)
Gastroschisis - where abdominal wall doesn’t close, herniation of intestine (better outcomes)
Hindgut formation
Posterior region of cloaca becomes anorectal canal
Anterior region becomes urogenital sinus
Urorectal septum separates the two
Anal canal - upper 2/3 from cloaca
- lower 1/3 from anal pit
Pectinate line between, as anal membrane breaks down
Anorectal fistula and atresia where anal canal fuses to urogenital canal, to uterus, or has no opening.
NICE criteria for IBS
Abdominal pain/discomfort and change in bowel habit \+ 2 of: - mucus - bloating - change in diet - excessive wind
Red flags on ‘IBS’ presentation
Weight/appetite loss
Blood in stool
Family history of bowel or ovarian cancer
Over 60, and 6 week change in bowel habit
Mass in abdomen or rectum
Needing to get up at night with abdominal pain/to use toilet
Classified as diarrhoea, constipation, or mixed
Diagnosis of IBS
Full blood count to look for inflammatory markers:
In blood - C reactive Protein, erythrocyte sedimentation rate
In faeces - calprotein
Causes of IBS
Diet (heightened immune response to some foods)
Genetics
Dybiosis (less diverse microbiota)
Inflammation - IBS can be triggered by infection
Visceral hypersensitivity
Psychological (stress)
Ensure not just dysmotility!
Treatment of IBS diarrhoea
Cut FODMAPS foods
Anti-diarrhoea medicine, immodium
Codeine, ondansetron
Colestiramina (for bile salt malabsorption)
Treatment of IBS constipation
Stop any causative drugs (eg opiates) Increase soluble fibre in diet Take fibre gels and sachets Amitiza, constella, senna, procalopride Avoid carbonated drinks
Managing pain in IBS
Expectations! Avoid opiates Low dose tricyclic antidepressants Dietary modification Hypnosis/CBT
Function of stomach in digestion
- 2L/day of secretions - pH 0.9-1.5, containing HCl, pepsins, intrinsic factor, mucus, HCO₃⁻
- Reservoir
- Digestion of proteins
- Absorption of vitamin B12
Cells in stomach produce:
G cells - gastrin Surface epithelial cells - mucus, HCO₃⁻ Mucus neck cells - mucus Parietal cells - HCl, intrinsic factor Chief cells - pepsinogens Endocrine cells - histamine, somatostatin
Secretion of HCl - by? function?
By parietal cells, when resting have tubulovesicles, and when active these are inserted into apical membrane, have canaliculus
HCl
- promotes activation of pepsins from pepsinogen
- kills/inhibits microorganisms
- stimulates secretions in the small intestine
- helps iron and calcium absorption in the small intestine
Secretion of HCl process
1- H⁺/K⁺ ATPase pumps H⁺ out and K⁺ in
2- K⁺ out across apical membrane into lumen
3- raised intracellular pH, so passive uptake of CO₂ and H₂O across basolateral membrane. Forms HCO₃⁻ and H⁺ via carbonic anhydrase.
4- HCO₃⁻ out, Cl⁻ in
5- HCO₃⁻ exit causes alkalinisation of local blood vessels -alkaline tide
6- Cl⁻ exits passively, so HCl secretion process
Na⁺/K⁺ ATPase and K⁺ channels maintain driving force for Cl⁻ exit
Agonists stimulating HCl secretion
INDIRECT
Histamine: Enteric neurone to ECL cell, releases Histamine, H2 receptor raises cAMP
DIRECT:
Gastrin: Enteric neurone to G cell, to ECL cell as above, and G cell makes gastrin, to CCkB receptor to raise cAMP
ACh: Enteric neurone releases ACh, to M3 receptor, raise cAMP
3 mechanisms allows for redundancy
Antagonist of HCl secretion
Somatostatin from D cells inhibits G and ECL cells, in the antrum of stomach
Intrinsic factor
THE ONLY GASTRIC SECRETION THAT IS ESSENTIAL FOR LIFE
Haptocarrin = Q factor, protects vitamin 12 in stomach but not in small intestine
IF is - glycoprotein secreted by parietal cells in stomach
- combines with vitamin B12 to resist digestion by pancreatic proteases
- facilitates absorption of vitamin B12 in ileum
Pepsins
Pepsins digest proteins to peptides
Optimal pH 3 or less
Chief cells secrete pepsinogens, which in contact with HCl to form pepsins
Gastric mucosal barrier
To protect against HCl and pepsins
- mucus gel
- HCO₃⁻
- surface epithelium impermeable to acid - tight junctionss
pH is 7 at mucus cells (high HCO₃⁻), 1.5 at gastric lumen, so creates mucus gel neutralisation zone
HCl doesn’t linger here, maintains high pH
Inhibition of HCO₃⁻ secretion (examples)
Aspirin
Adrenaline
Noradrenaline
So can cause gastric ulcers
Prostaglandins effect on gastric secretions
Increase HCO₃⁻ Increase mucus Decrease HCl Increase blood flow to mucosa Modify inflammatory response
Gastric secretions in cephalic phase
Sight, smell, taste activate vagus nerve
–>
STIMULATES: ECL cell -> histamine -> parietal cell
Enteric neurones -> G cell -> ECL cell - - ->
INHIBITS: D cell
- entirely dependent on vagus nerve
- 20% total secretions
- before food enters stomach
Gastric secretions in gastric phase
STIMULATION:
Distension -mechanoreceptors-> Parietal cell + G cell
Digested proteins+amino acids -chemoreceptors-> G cell -> secretory cell
INHIBITION:
HCl -chemoreceptors-> D cells, which INHIBIT G and parietal cells
Gastric secretions in intestinal phase
First stimulates, then inhibits
STIMULATION when gastric chyme pH>3:
Distension of duodenum -mechanoreceptors-> G and parietal cell (antrum of stomach)
Digested proteins+amino acids -chemoreceptors-> G cell -> parietal cell (duodenum)
INHIBITION when gastric chyme pH<3
HCl -> secretin and D cell, inhibits ECL, G, Parietal cell
Products of digestion -> CCK and GIP, inhibit Parietal and G cell
Gastric motility
Receptive relaxation - fundus and body act as reservoir
- vasovagal reflex: food, mechanoreceptors, vagal, CNS, vagal, relaxation
Contraction - peristalsis in body and antrum to mix food with secretions
- tonic contraction in pylorus to control emptying of food into duodenum, maintained contraction over minutes or hours
Gastric repropulsion = peristalsis
Contractions begin in body, travel towards pylorus
Increase in force and velocity as they approach the gastroduodenal junction
Most mixing occurs in antrum
Function is to mix and break down gastric contents, must be <2mm diameter to get through pylorus
Rate of gastric emptying
Pressure difference between lumen of stomach and duodenum is driving force
Carbohydrates fastest, then proteins, fats slowest
Solution faster than solids
Rate controlled by neural and hormonal regulation.
Gastric emptying to duodenum slowed by:
Hypertonic solutions
HCl
Fatty acids, monoglycerides
Amino acids, peptides
As need more time to digest. The rate will not exceed the rate at which i) acid can be neutralised ii) fat can be emulsified iii) small intestine can process chyme
Do also increase activity and digestion in small intestine.
Treatment related causes of nausea and vomiting
Chemotherapy
Radiotherapy to brain, stomach, bowel, near liver
Hormonal therapies
Morphine-based pain killers
Anti-Emetics
Inhibit chemical trigger zone - toxins, drugs, vestibular nuclei labyrinth comes through here
Inhibit D₂ or 5HT₃ receptors
D₂ dopamine receptor antagonists
Anti-emetics to inhibit CTZ
Prevent vomiting by agents which trigger CTZ
Also sedative, so used in motion sickness
CHLORPROMAZINE, ACEPROMAZINE
METACLOPRAMIDE
Also antagonises 5HT₃ receptors, so very potent
+ peripheral action, increases muscle tone in LES to prevent vomiting
5HT₃ receptor antagonists
Anti-emetics to inhibit CTZ
ONDANSETRON
NABILONE
5HT₄ agonists
Anti-emetics to inhibit CTZ
CISAPRIDE
Acts peripherally, increases gastro-oesophageal sphincter contraction and GI motility
Now withdrawn -> long QT syndrome
Corticosteroids
Anti-emetics to inhibit CTZ
DEXAMETHASONE
H₁ Histamine receptor antagonists
Anti-emetics to inhibit vestibular nuclei and nucleus of solitary tract (labyrinth receptors)
DIPHENHYDROMINE
CYCLIZINE
PROMETHAZINE
Effective in motion sickness, and morning sickness (pregnancy)
Anti-muscarinic activity also
Muscarinic ACh antagonists
Anti-emetics to inhibit vestibular nuclei and nucleus of solitary tract (labyrinth receptors)
HYASCINE
Effective in motion sickness
Emetics
Stimulate vomiting
IPECACUANHA - irritant to stomach lining
APOMORPHINE - D₂ agonist
Diarrhoea
2L water is ingested, + 7L secretions enter GI tract daily
-> so lots of water needs to be absorbed!
Diarrhoeas if hypersecretion or reduced absorption due to - infection, toxins, chronic inflammation, dietary imbalance
Dangerous in neonates/the elderly as causes dehydration and acidosis
Treat with rapid rehydration and electrolytes, antibiotics, absorbents?
Normal absorption of electrolytes and water
1 - Apical active cotransport of Na⁺ and glucose in
2 - Na⁺ out, K⁺ out via Na/K ATPase on basolateral membrane to maintain gradient
3 - Cl⁻ in via apical channels
4 - Osmotic pressure created, water moves paracellularly into blood
Cholera mechanism
Cholera toxin causes GM1 receptor to be internalised by retrograde endocytosis
Increases cAMP
Activates CFTR, so Cl⁻ leaves cell
Draws Na⁺ and water out also -> RAPID REHYDRATION
Treatment of cholera
Antibiotics against cholera bacterium
Inhibit GM1 target receptors
Decrease adenylate cyclase, so decrease cAMP
Inhibit CFTR, so decrease Cl⁻ loss
Drugs to treat diarrhoea
ANTIMUSCARINICS - short term use for pain relief, decrease peristalsis BUT also segmental contractions
OPIOIDS - slow peristalsis, and increase segmental contractions (good), so increased fluid absorption
– these are motility modifying drugs, allow more time for reabsorption of water –
ANTI-INFLAMMATORY AGENTS - eg sulphasalazine
CORTICOSTEROIDS - eg prednisolone, dexamethazone
Causes of constipation
Slow motility of colon
Too much water removed by colon
Weak abdominal muscles
Diet
Treatment of constipation (laxatives)
LUBRICANTS
- liquid paraffin - good but lines mucosal surface so may prevent absorption of some fat soluble vitamins
BULK FORMING DRUGS
- sterculia - increase volume of non-absorbable food in colon, but need high fluid intake!
INTESTINAL STIMULANTS
- bisacodyl, dantron, phenolphthalein - stimulate contraction, may cause abdominal cramps. Don’t use if possible obstruction!
OSMOTIC LAXATIVES
- MgSO₄, lactulose - poorly absorbed solutes remain in GI tract, so promote movement of water into lumen
Protective factors against peptic ulcers
Mucous gel
HCO₃⁻
Prostaglandins (stimulate mucus and HCO₃⁻ production in surface E cells, decrease HCl release from parietal cells)
Goals for management of peptic ulcers
Address primary problem, antibiotics?
Decrease acid secretion and increase mucus production
H₂ receptor antagonists
To treat peptic ulcers
(HCl secretion is stimulated by histamine)
CIMETIDINE
RANITIDINE
Decrease basal and food stimulated acid secretion
Decrease volume of gastric juice, decrease [H⁺]
Muscariric receptor antagonists
To treat peptic ulcers
(HCl secretion is stimulated by ACh)
PIRENZIPINE
Decrease basal and food stimulated acid secretion
Decrease volume of gastric juice, decrease [H⁺]
Proton pump inhibitors
To treat peptic ulcers OMEPRAZOLE ESOMEPRAZOLE LANSOPRAZOLE Irreversibly inhibit H⁺/K⁺ proton pump Inactivated at neutral pH, short plasma half life so not detected in plasma even when active, but accumulates in areas of low pH so is long lasting
Antacids
To treat peptic ulcers
SODIUM BICARBONATE (-> gas as produce CO₂)
ALUMINIUM AND MAGNESIUM SALTS - react with HCl to form insoluble colloid. Give both to -> normal bowel function.
Aluminium salts -> constipation
Magnesium salts -> diarrhoea
(alphabet)
Mucosa protecting drugs
For peptic ulcers
SUCRALFATE (inc aluminium salts, so is constipating)
- forms gel with mucosa to coat and protect
BISMUTH CHELATE - coats ulcer base
- absorbs pepsin
- enhances prostaglandin synthesis
- increases HCO₃⁻ secretion
Misoprostol
For peptic ulcers caused by NSAIDs
Synthetic prostaglandin
Acts on parietal cells to decrease acid secretion
Increases blood supply
Increases mucus and bicarbonate secretion
Secretions from liver
0.5L/day
pH 7.4
Bile acids, cholesterol, phospholipids
For digestion and absorption of fats
Secretions from small intestine
1L/day
pH of 7.6
Mucus, enteropeptidatse (=enterokinase, doesn’t phosphorylate, to activate proteases from pancreas), water
Secretions from pancreas
1.5L/day
pH of 7.8-8.4
Contains salts (sodium bicarb mainly) and enzymes
Endocrine and exocrine function of pancreas
ENDOCRINE Insulin and glucagon EXOCRINE - salts and water (HCO₃⁻, NaCl, water = pancreatic juice) to create correct environment for enzyme action - enzymes: -- proteases to digest proteins -- lipases to digest fats -- α-amylase to digest carbohydrates
Secretion of enzymes from pancreas
Made in rough ER -> golgi -> condensing vacuoles -> zymogen granules for storage
Lipases and α-amylases are released as active enzymes, as can’t damage the pancreas
Proteases (trypsin, chymotrypsin, carboxypeptidases) are released as inactive zymogens (trypsinogen, preCP etc)
Released packaged with with (trypsin) inhibitor to stop premature activation
Enteropeptidase is bound to brush border of apical membrane of duodenum and jejunum andwill activate later
Exocytosis of zymogens from pancreas caused by
CCK and M3 receptor neurones trigger IP3 and DAG
Secretin -> cAMP
Secretion of salts and water by pancreatic duct cells
Stimulated by secretin
- Na out/K in pump creates inward Na⁺ gradient
- Na⁺/HCO₃⁻ cotransporter and intracellular generation of HCO₃⁻ from CO₂ and H₂O -> HCO₃⁻ accumulates inside
- H⁺ removed via Na/H exchanger
- Cl⁻/HCO₃⁻ exchanger secretes HCO₃⁻ to lumen
- cAMP stimulated Cl⁻ channels (CFTR) secrete Cl⁻
- K⁺ exit maintains driving force for Cl⁻ exit
- HCO₃⁻ exit -> Na⁺ and water drawn through paracellular pathway to duct, NaHCO₃ secretion
Control of pancreatic secretion
Cephalic phase - stimulated by vagal impulses
Gastric phase - vasovagal reflexes following distension -> high enzyme volume
Intestinal phase - acid detection by S cells - -> secretion of large volume, low in enzyme conc
- fatty acids, monoglycerides, peptides -> CCK - -> enzyme rich pancreatic juice
- distension and osmolarity -> mechanoreceptors
Components of bile
Secreted by hepatocytes and stored in gallbladder
- 65% bile acid - emulsify lipids
- 20% phospholipids
- 4% cholesterol
- 0.3% bile pigments
Enterohepatic circulation
Happens multiple times per day, more if after a protein/fat rich meal
- bile acids reabsorbed from ileum
- reabsorbed bile acids are returned to liver and taken up by hepatocytes
- bile acids in blood stimulate uptake and release of bile acids from hepatocytes, but inhibit the synthesis of new bile acids
Secretions of epithelial cells in small and large intestines
Mucus - protect mucosa, lubricate intestinal contents (from Brunner’s glands in SI and crypts of Lieberkuhn in LI)
Alkaline aqueous secretions - buffer gastric acid
Enterokinase/peptidase - activate zymogens to proteases
1L/day
pH 7.6
Isotonic (same osmolarity as plasma)
Small intestine vs large intestine
6m long SI, 2.4m LI 300m² surface area SI, 25m² LI No villi in LI, flat surface with crypts (yes microvilli) No nutrient absorption in LI No active K⁺ secretion in SI
Active K⁺ secretion in large intestine
Na/K ATPase, NKCC1 and K⁺ channel in basolateral membrance bring K⁺ in
Apical K⁺ channel for K⁺ out, stimulated by cAMP
Aldosterone upregulates the number of all protein channels
Electrical activities in small intestine
SLOW WAVE
Intrinsic activity
Duodenum most frequent, ileum slowest
ACTION POTENTIAL BURSTS
Only in short localised segments of intestine
-> segmentation
Regulated by hormones, autonomic and enteric NS
(parasymp increases enteric, symp decreases enteric)
Function of colonic contractions
To mix chyme, increase absorption of water and salts
Knead semisolid contents
Move contents towards anus -> segmentation
Mass movement/peristalsis - due to gastrocolic reflex, stimulated by distension of stomach
Directly controlled by enteric neurones
Absorption in the small intestine
Food remains in small intestine for 3-8 hours
Fat digestion products (water, water- and lipid-soluble small molecules) move by facilitated transport
Carbohydrates and proteins absorb by facilitated transport
Carbohydrates also absorb by active transport
Larger molecules absorb by endocytosis
Digestion and absorption of carbohydrates in small intestine
Mainly in duodenum, then jejunum, then ileum
Carbohydrates (amylopectin, glycogen, cellulose)
- α-amylase -
- > Oligosaccharides (α-dextrin, di- and trisaccharides)
- > Glucose, galactose, fructose
Digestion of oligosaccharides at brush border
4 enzymes in 3 functional units:
SUCRASE-ISOMALTASE - S - maltose, maltotriose, sucrose -> glucose + fructose
- I - maltose, maltotriose, α-limit dextrins -> glucose monomers
MALTASE - maltase, maltotriose -> glucose monomers
LACTASE - lactose -> galacatose + glucose
These enzymes are NOT rate limiting, transporters on apical membrane are
Absorption of carbohydrate breakdown products from lumen into epithelial cells
SGLT1 (sodium coupled glucose cotransporter 1) for glucose, galactose
GLUT5 for facilitated diffusion of fructose
Absorption of carbohydrate breakdown products from epithelial cells to interstitial space
GLUT2 for facilitated diffusion of glucose, galactose and fructose
Absorption of protein in small intestine
Mainly in duodenum, then jejunum, then ileum
Proteins
- proteases -
- > amino acids, tripeptides, dipeptides
Amino acids diffuse straight into cell
Di/tripeptides cotransported in with H⁺, then peptidases break down to form amino acids intracellularly
Amino acids transported out by Na⁺ independent transporter into blood.
(many mechanisms for amino acids into cell, some use H⁺ and Na⁺ as cotransporters)
Digestion and absorption of fat in small intestine
Mainly in jejunum, then duodenum, then ileum
Bile acids emulsified to form emulsion droplets, then form free fatty acids and monoglycerides when mixed with pancreatic lipase
Free fatty acids combine with phospholipids, cholesterol and bile acid micelles to form a mixed micells
Mixed micelle moves to unstirred acid layer, to chylomicron in epithelial cell, to lymph duct
Absorption of Na⁺ in small intestine, different methods into cell
1 - cotransport in with glucose or amino acid via SGLT1
2 - exchanged for H⁺ (stimulated by HCO₃⁻ in lumen)
3 - Na/H works with Cl⁻/HCO₃⁻ in fasting state
4 - diffusion across simple Na⁺ transporter
Absorption of Cl⁻ in small intestine, different methods into cell
1 - Voltage gated Cl⁻ channels
2 - Cl⁻/HCO₃⁻ works with Na/H in fasting state
Cl⁻ secretion in crypts is stimulated by cAMP, via CFTR
Absorption of water soluble vitamins
B1 (thiamine) B2 (riboflavin) Niacin C Folic acid B6 B12
All diffusion by facilitated transport, cotransported with Na⁺ receptor-mediated endocytosis
Absorption of fat soluble vitamins
A
D
E
K
Diffusion facilitated by bile
Vitamin B12 absorption
With R factor (haptocorrin) in stomach
With intrinsic factor in small intestine, combine and use IF-B12 receptor complex
Functions of the colon
Absorption of water (1.9L/day - 2L in, 100ml out in stool)
Storage
Mass peristalsis
Some nutritional role?
Anorectal function
Reservoir
Pelvic floor muscles act as sling to support bowel - internal anal sphincter gives resting tone, external anal sphincter is skeletal, under own control via pudendal nerve
Diagnosis of constipation
Infrequent bowel movements (normal varies - 3 in 1 day or 1 in 3 days)
Straining
Passing of hard stool
Loaded colon palpable
Only a problem if its a problem for the individual
More in women than men
Investigations for constipation
- Flexible sigmoidoscopy to rule out organic disease (non-functional), eg obstruction, cancer
- Blood tests to rule out metabolic disorders (hormonal imbalance)
- Swallow radio markers and Xray for next 3 days to measure colonic transit
- Proctography (evacuation)
Evacuatory disorders
Includes slow transit constipation, normal transit constipation, outlet obstruction
Usually outlet obstruction
Often post menopausal women who have had vaginal births, pelvic floor weakness (or no uterus)
Anismus = inappropriate gate closing
Normal defecation
Propulsive colonic contraction
Sensation of ‘call to stool’
- correct environment and posture important -
Raised intrabdominal pressure
Relaxation of striated muscle of pelvic floor
Opening of anorectal angle
Disordered sensation
= No sensation that bowels are filling, so ignore call to stool
-> megarectum, rectum so enlarged that it pushes organs away and distends belly
Due to spinal problems, or can be acquired behaviour
Internal anal sphincter dysfunction
Rectoanal inhibitory reflex exists to move stool close to anus, so can detect how much there and what consistency, then it moves stool back again
Hirschsprungs = no detection, so leakage.
OR constant closure, can’t pass stool.
Anismus
Increased recruitment of striated muscle in pelvic floor
Inappropriate gate closing
No relaxation for defecation, contracting against shut gate is very painful
Evaluating evacuatory disorders
Obstetric history (prolonged childbirth, use of forceps etc) History of abuse or psychological reasons for delaying defecation Examination Investigations - anorectal physiology, defecating proctography (contrast into rectum, defecate in front of Xray - unreliable, as often anxious/embarrassed), colonic transit test
Management of evacuatory disorders
Conservative, usually no surgery. Multidisciplinary:
Dietary advice
Laxatives (if long term, may desensitize bowel)
Establish routine
Suppositories/enema to self manage
Squatting posture
Biofeedback - attempt to train pelvic floor relaxation, EMG or manometric feedback devices
Surgery:
Subtotal colectomy and ileorectal anastomosis - remove all colon and plumb SI onto rectum
Ventral mesh retropexy - put mesh in, to lift and support bowel. Risk of erosion into vagina and rectum
STARR - cut away the donut of bowel not working and stitch back
Faecal incontinence causes
Obstetric injury Trauma Iatrogenic Neurological Overflow from severe constipation
Management of faecal incontinence
Loperamide syrup to make stool more solid, easier control
Suppositories/enema - maybe use just before leaving house if only leaving ~2 per week
Colonic irrigation, can be daily
Surgery - anterior repair of external anal sphincter, gracilis neosphincter (muscle from leg), artificial bowel sphincter, sacral nerve stimulation at pudendal origin (SNS - easy, low risk, expensive)
Disorders of absorption definitions - malabsorption, malnutrition
Malabsorption - Failure of the intestinal processes of digestion, or transport across the intestinal mucosa into the systemic circulation
Malnutrition - Deficiency of nutrients causes measurable adverse effects on tissue composition, function or clinical outcome
Intestinal failure
A reduction in functioning gut mass to below amount required for adequate digestion and absorption of food.
Type I - self-limiting - eg after handling in surgery or infection, is floppy, atonic, bloated, can’t eat - settles on its own
Type II - severe, requiring temporary support - eg if stomach removed, need total parenteral nutrition (TPN) or jejunual feeding tube
Type III - chronic, requiring long term nutritional support - eg if small bowel infarction
Have vs need of small and large bowel
Have 6m small bowel, need 120cm
Have 1m large bowel, need none
Mechanisms of absorption
Luminal processing - carbs, fats and proteins hydrolysed and solubilised (pancreatic and biliary action)
Mucosal absorption - uptake of saccharides and peptides, lipids processed and packaged for cellular export
Transfer into circulation - absorbed nutrients enter the vascular or lymphatic circulation
Presenting features of a disorder of absorption
Diarrhoea Weight loss Pain/bloating (inflammation or obstruction) Anaemia (Fe/B12/folate deficiency) Neurological symptoms Bleeding (K deficiency) Metabolic (calcium, D deficiency)
Causes of malabsorption
COMMON Resection Fistula Inflammation Coeliac disease RARE Small bowel diverticulitis Whipple's disease Pancreatic exocrine insufficiency Parasitic infection
Vitamin B12 deficiency
If terminal ileum removed, lose intrinsic factor
Pernicious anaemia is autoimmune
So loss of gastric parietal cells and associated intrinsic factor
Pancreatic exocrine insufficiency
Insufficient production of amylase lipase and protease, causes steatorrhoea and malabsorption
Diagnosed with - faecal fat, faecal elastase, cross sectional imaging
Crohn’s disease
Inflammatory bowel disease, like ulcerative colitis
Chronic inflammatory disease of the intestine
Occurs anywhere from mouth to anus, mainly small intestine and colon
Patchy inflammation with ulceration (discontinuous)
Transmural, all layers of gut affected
Peaks of incidence at 15-25 and 50-60 yo
More common in northern latitudes and developed nations
Symptoms of Crohn’s disease
Pain - constant, or in waves as peristalsis tries to push down
Diarrhoea - may be bloody
Weight loss - due to loss of appetite and poor absorption
Fatigue (partly due to anaemia, hard to treat)
Rectal bleeding
Causes of IBD
Genetics - NOD2/CARD15 gene mutation has 40x increased risk. Polygenetic influence
Gut bacteria - reduced diversity, adherent invasive E coli
Immune system
Environment
Features of Crohn’s
Abnormal mucus (thick in crohn’s, thin in UC)
Abnormal permeability (leaky bowel wall) - tight junction defects, may be secondary to inflammation
Autophagy - to provide nutrients under starvation conditions and kill ingested bacteria
Dysregulated inflammation - more recruitment of inflammatory cells
Treatment for Crohn’s disease
- Glucocorticoids (not long term as side effects)
- Bowel rest by diet or diversion - eg elemental diet of amino acid cocktail
- Immunosuppressives - AZATHIOPINE (to decrease T cell proliferation) and METHOTREXATE
- Surgery to remove diseased bowel segment (but 2/3 people will have reoccurence at join)
- Biological agents - anti TNF - expensive and effects will wear off
Investigations of the GI tract
Xray used for all sites, fast and cheap
CT/MRI for better detail, especially in trauma
Oesophagus, stomach and duodenum - endoscopy, barium swallow
Small bowel - MRI, barium meal
Colon - colonoscopy
Key radiological signs
Narrowed ileum - Crohn’s
Apple core - carcinoma
Coiled intestine - intussusception
Definitions: Hyperplasia Hypertrophy Metaplasia Dysplasia
Hyperplasia - increase cell number by mitosis
Hypertrophy - increase cell size
Metaplasia - acquired form of altered differentiation (to different cell type
Dysplasia - abnormal growth and differentiation of a tissue, often pre malignant
Risk factors for oesophageal tumours
GORD Use of antacids Caustic injury Cigarettes Alcohol Stricture Achalasia Barrett's oesophagus (normal stratified squamous epithelium lining is replaced by simple columnar epithelium, response to reflux from below)
TNM staging - Tumour
T0: no cancer
Tis: carcinoma in situ, only in top layer
T1: in lamina propria and the submucosa
T2: in muscularis propria, into but not through the muscle wall
T3: in adventitia, through the entire muscle wall into surrounding tissue.
T4: outside the organ into areas around it, eg aorta, trachea, diaphragm, pleural lining of lung
TNM staging - Node
N0: not in any lymph nodes
N1: spread to 1 or 2 lymph nodes nearby
N2: spread to 3 to 6 lymph nodes nearby
N3: spread to 7 or more lymph nodes nearby
TNM staging - Metastasis
M0: The cancer has not spread to other parts of the body
M1: The cancer has spread to another part of the body
Risk factors for gastric cancer
High salt, low dairy diet Helicobacter Intestinal metaplasia Pernicious anaemia Family history
Risk factors for colorectal cancer
Age Polyps Sedentery lifestyle Poor diet - high red meat, low dairy, garlic, vegetables Obesity Alcohol Family history Inflammatory bowel disease Hereditary syndromes - Familial adenomatous polyposis (FAP) and Hereditary non polyposis CRC (HNPCC) Raised inflammation
Development of CRC
Normal epithelium - stimulation of proliferation in basal crypt - Hyperproliferation - proliferation in upper crypt - Early adenoma - inhibition of apoptosis in upper crypt - Intermediate adenoma Late adenoma - growth factors - Cancer
Colorectal polyps
Protuberant growths of epithelial or mesenchymal origin
Neoplastic or non neoplastic, benign or malignant
- inflammatory
- hamartomatous
- neoplastic
95% of CRC arises from adenomas - increased risk if bigger, more numerous, more villi, more dysplastic
Familial adenomatous polyposis (FAP)
Autosomal dominant Germline mutation in APC > 100 polyps, start to appear as teenager CRC in 40s-50s Surgery or chemoprevention to remove
Hereditary non polyposis CRC (HNPCC)
= lynch syndrome
Defect in mismatch repair genes (MMR)
Multiple tumours but no polyposis
CRC diagnosed aged 45 ish, 80% will get CRC
Infective gastroenteritis
Mainly viral, or can be bacterial or parasitic
Toxins, cell lysis from viral invasion, tissue damage, inflammation etc -> increase peristalsis and damage villi to disrupt absorptive capacity
Rotavirus
Main worldwide cause of gastroenteritis in children (most will have before age 5, so immune to that strain)
Virus - wheel shaped, non-enveloped, many strains
Transmitted faeco-orally, very contagious
Symptoms - diarrhoea, vomiting, cramps, fever
Norovirus
Main worldwide cause of gastroenteritis in adults (and children in UK)
Peaks in winter months (vomiting bug)
Frequent recombination, so many diverse strains
Transmitted via food and water (shellfish especially), aerosol person-person
Don’t retain immunity for long
Often outbreaks in institutions
Abrupt onset, highly infectious
Symptoms - nausea, vomiting, diarrhoea, low fever, myalgia
Treatment of gastroenteritis
Infection control!
Rehydration by IV fluids
Antibiotics if immunocompromised bacterial infection
Inform HPA of notifiable disease
Escherichia coli
Range of strains, some commensal, some highly pathogenic
O or H antigens
-> gastroenteritis, UTIs, bacteraemia
E coli O157 strain
Produces verocytotoxin
Causes gastroenteritis -> blood diarrhoea, abdominal tenderness
Can -> HUS (haemolytic uraemic syndrome): renal failure, haemolytic anaemia, thrombocytopenia
Transmitted by contaminated food and water, zoonosis in direct animal contact
Shigella
Invades colonic mucosal cells and releases toxins eg shiga (inhibits protein synthesis, cell detah, vascular damage)
Very contagious (low infective dose needed)
Transmitted person-person, food/water. Common in overcrowding.
Causes gastroenteritis -> abdominal cramps, mucoid/bloody diarrhoea (dysentry), fever, vomiting
Campylobacter jejuni
Most common cause of bacterial gastroenteritis
FOOD POISONING, often undercooked meat, zoonotic
Increasing prevalence with antibiotic use in farm animals -> resistance
Abrupt onset of abdominal pain, then diarrhoea (bloody/mucoid), vomiting
Can cause GI haemorrhage following bacteraemia, toxic megacolon, reactive arthritis, Guillian-Barre syndrome
Salmonella
Inc S. typhi (typhoid fever)
Food/water bourne, faeco-oral, zoonotic in reptiles
FOOD POISONING
-> vomiting, bloody diarrhoea, fever, cramping, or typhoid fever is more systemic
Non typhoidal is self limiting usually, typhoid fever needs IV cetriaxone (typhoid vaccine in endemic areas)
Bacillus cereus
FOOD POISONING
Spores survive heating, germinate when rice kept warm
Ingestion of toxin stimulates adenylate cyclase, increasing water and electrolyte secretion, vagal nerve stimulation
Clostridium botulinum
Neurotoxin (most potent)
Blocks release of ACh at NMJ, mainly in peripheral NS
FOOD POISONING (often from poor canning procedures)
or wound botulism (often IV drug users)
or infant botulism
Causes GI symptoms, progressing to descending flaccid paralysis
Fatal 10% due to respiratory or cardiac failure, or slow recovery (months)
Treat in intensive care for organ support, antitoxin
Clostridium difficile
Main antibiotic-associated diarrhoea
In 3% healthy adults
Thrives in disruption of normal gut flora following antibiotics
Toxins -> fluid secretion, mucosal inflammation, cell damage
Spores into air, so vulnerable hospital patients will get
(-> pseudomembranous colitis)
Vibrio cholerae
Inhabit salt water worldwide
Transmitted by infected food or water (often shellfish), or faeco-oral
Needs high infective dose (not very infectious)
Endotoxin activates adenylate cyclase, so mass water and electrolyte loss into gut lumen
-> profuse ‘rice water’ diarrhoea
50% mortality if untreated
Giardia lamblia
Flagellated protazoa (parasite)
Can be asymptomatic, or gastroenteritis symptoms
Treat with METRONIDAZOLE
Entaemoba histolytica
Flagellated protazoa (parasite)
Can be asymptomatic, or gastroenteritis symptoms
Treat with METRONIDAZOLE
Cytosporidium
Protazoan
Common in AIDs patients
Waterbourne, ingest eggs (oocysts)
Cytomegalovirus (CMV)
Herpes viridae family
Lies dormant and reactivates when immunosuppressed
Infects many cell types
Glandular fever like presentation
Helicobacter pylori
Adapts to gastric conditions by producin urease to neutralise gastric acid
-> chronic gastritis, peptic ulcers, gastric adenocarcinoma, lymphoma
Important to know pharmacokinetics
- need to know if drug will be absorbed if given by a specific route
- need to know where drugs go inside the body, to which receptors
- dosage
- drug metabolites
Major routes of drug administration - ENTERAL (to GI tract)
Oral - easiest, but only if willing to take (awake), and is slow acting, 1st pass metabolism as goes via liver
Sublingual - rapid, but only few drugs can cross mucous membrane into blood
Rectal - good as can be administered if eg seizing, sometimes easier than IV (small children), local effects only so few side effects
Major routes of drug administration - PARENTERAL
IV - rapid, as no absorption needed, but sometimes difficult access and sometimes infection
Intramuscular - can control rate of release if packaged in oily vehicle, but very painful
Subcutaneous - easy to self administer
Inhalation - large SA in lungs for absorption, but technique required
Intranasal - local or general effect, easy even with children
Locally - epidural, intravaginal, intraarticular, eye drops, creams, transdermal patches etc
Oral bioavailability
Fraction of orally administered drug that is absorbed into the systemic circulation
= 1 if all drug given is absorbed into circulation following oral administration
Reduced if - poor absorption from gut, breakdown of drug in gut, first pass effect (drug passes liver before going into systemic circulation, so enzymes can break down drug and reduce availability)
Factors effecting drug absorption at a membrane
Lipid solubility of drug - drugs need to cross membranes by passive diffusion, so high lipid solubility -> more likely to be absorbed
pKa of drug (pH at which it is 50% ionised)
pH at absorbing surface
Area of absorbing surface
Rate of blood flow to other side of absorbing surface
Rate of dissolution of preparation
Ion trapping
Most drugs are either weak acids or weak bases, so exist ionised or unionised depending on pKa and pH of solution
Membranes separate solutions of different pH as only unionised can cross, so trap some
Drugs are rarely strong acids, as they would always be ionised and would never cross membranes
Use pH = pKa + log ([ionised]/[unionised]) to calculate rate for different locations - eg if low number then more unionised than ionised, so good absorption from (stomach), vs high number in plasma so drug stays —> ion trapping
Drug distribution
= Penetration of drug into tissues and organs from the blood
Degree of distribution depends on lipid solubility and extent of plasma protein binding
Measured with Vd (Apparent volume of distribution)
Vd (Apparent volume of distribution)
= the volume of water in which the drug would have to be distributed to give its plasma concentration
To measure drug distribution
Vd = amount of drug in body / concentration in plasma
- expressed as volume or volume/mass
Helps determine plasma half life of drug, can be used to design dosing schedules
Drug elimination
= excretion + metabolism
(excretion in bile, urine, vomit, faeces, milk)
(metabolism in liver mainly, metabolites out to urine)
Half life of drug
t₀.₅ = the plasma half life of a drug, the time it takes for the plasma concentration of a drug to fall to half of its initial value
Quantification of elimination
= clearance x Cp (plasma concentration)
Clearance
Clearance = rate of elimination / plasma concentration
Clearance is the amount of plasma which is cleared of its drug content in unit time
Useful measure, as rate of elimination varies with Cp whilst clearance stays constant
(Rate of elimination increases with increased Cp)
Kinetics of drug elimination - zero order
Straight line diagonally down
Process is rate independent of drug concentration, t₀.₅ varies depending on how much drug is administered
Elimination rate is saturated
Few drugs
Kinetics of drug elimination - pseudo-zero order
Zero order (straight line) at high concentrations Then at lower concentrations, no longer saturated so becomes first order
Kinetics of drug elimination - first order
Most common, with constant half life
drug absorption into blood is also usually first order
Drug elimination equations
Ct = C₀ x e⁻ᵏᵗ
Ct = plasma conc at time t C₀ = plasma conc at time 0 k = rate constant of elimination
t₀.₅ = (0.693 x Vd) / clearance
Vd = volume distribution
More complicated clinically! Different rates into different tissues
Css
Css = steady state concentration, where rate of infusion = rate of elimination
Eliminated by first order process
Rate of elimination increases with increasing Cp
At steady state: Rate of elimination = Css x clearance
Rate of infusion
Rate of infusion = Css x clearance
(as infusion rate = elimination rate)
Takes 5 half lives to reach Css, regardless of infusion rate, and then 5 half lives to return to 0
A loading of infusion before a maintenance infusion ensures therapeutic effects quickly, and avoids wiggly oral dosing line
Oral dosing
Cssₐᵥ = DxF / TxCl
Steady state average = individual dose x oral bioavailability / time interval between doses x clearance
With fewer but larger doses, there is more variation in Cp, but too many small doses are inconvenient
Drug excretion via the kidney influenced by:
1 - glomerular filtration, for free drug not bound to protein
2 - active secretion of drugs and metabolites (pump, eg penicillin)
3 - passive reabsorption, for all lipid soluble drugs
So only non-lipid soluble drugs and metabolites end up in urine
So reduced renal function will prolong plasma half life of drug, and get to higher steady state plasma concentrations.
If drug eliminated by hepatic metabolism, reduced renal function will have no effect, and vice versa.
Hepatocytes
Arranged into lobules, with a central vein in the middle and a triad of hepatic portal vein, hepatic artery and bile duct at each corner
Periportal hepatocytes - close to corners, get blood rich in nutrients
Perivenous hepatocytes - close to centre, blood supply is depleted of nutrients
So cells have different metabolic profiles
Liver diseases
Non-alcoholic fatty liver disease (obesity)
Alcoholic fatty liver disease, toxin induced
Hepatitis
Cancer
Autoimmune disease
Inborn error, enzyme disorders
-> cirrhosis and metabolic disturbances, response to injury or death of some liver cells by the production of interlacing strands of fibrous tissue between nodules of regenerating liver. Sometimes reversible (eg alcoholic)
Roles of liver, and consequence of disease
Carbohydrate metabolism - fasting hypoglycaemia
Lipid metabolism - fatty liver
Amino acid metabolism - hyperammonaemia
Serum protein synthesis - low serum albumin, impaired blood clotting
Metabolism and secretion of xenobiotics - impaired drug metabolism, hyperbilirubinaemia
Role of liver in glucose homeostasis
FED STATE -> glycolysis
Uses glucokinase, low affinity for glucose (so picks up if high concentrations)
FASTED STATE -> gluconeogenesis
Uses glucose-6-phosphatase, only present in liver and kidney
Cori cycle
In muscle, glycogen -> lactate, losing ATP in glycolysis to allow rapid contraction
In liver, lactate -> glycogen, gaining ATP to use in gluconeogenesis during recovery
Lipid metabolism in liver
- storage of fatty acids as TAG in liver cell
- oxidation of free fatty acids to generate AcCoA
- oxidation of AcCoA by the citric acid cycle
- generation of ATP by oxidative phosphorylation
FASTING - production of ketone bodies to be exported and used by other tissues
FED - conversion of AcCoA to cholesterol - export and import of free fatty acids, which will then bind to albumin in the blood
- export of TAG as VLDL
- synthesis of free fatty acids from glucose
Fatty liver disease
TAG accumulates as intracellular fat droplets, steatosis
Liver is not designed to store much TAG, so compromised function -> steatohepatitis
Amino acid metabolism
Excess amino acids cannot be stored, so their metabolism/degradation takes preference over that of excess carbohydrate and fat
Ammonia is immediate natural breakdown product, highly toxic
Destination of dietary protein
Dietary protein
↓
Amino acids
↓
(options)
1) synthesis to cell proteins
2) exported
3) synthesis of other cellular components
4) transamination/deamination, and synthesis of urea
5) gluconeogenesis from carbon skeleton
6) entry to the citric acid cycle, produce CO₂
7) conversion to AcCoA, then to fatty acids
8) alanine cycle
Alanine cycle
In muscle, glucose -(glycolysis)-> pyruvate -> alanine
In liver, alanine -> pyruvate -(gluconeogenesis)-> glucose
Alanine is a source of power for gluconeogenesis, providing a carbon skeleton and transporting NH₄⁺ in a non toxic form
Hyperammonaemia
Where blood ammonia > 10μm
Hepatic ammonia comes from:
- gut - bacterial action on nitrogenous compounds and glutamine metabolism by intestinal cells -> NH₄⁺
- liver - dietary amino acids -> NH₄⁺
- muscle - protein -> amino acids -> alanine, glutamine -> NH₄⁺
SO high ammonia in portal vein
Hepatic encephalopathy
Where blood ammonia > 50μm
Associated with advanced liver disease
-> disorientation, confusion, lethargy, coma, death
Consequence of severe hyperammonaemia, hypoglycaemia and accumulation of other toxic substances
Interferes with function of GABA in neurotransmission, with brain metabolism and causes changes in structure and morphology of brain
Deamination of amino acids in liver
To form α-keto acids, α-ketoglutarate (-> pyruvate)
Using aminotransferases (alanine ALT and aspartate AST). An increase in these indicates liver damage!
Also uses glutamate dehydrogenase and glutaminase
Fate of glutamate in liver
1) Oxidative deamination via glutamate dehydrogenase to produce NH₄⁺
Glutamate + NAD -> α-ketoglutarate + NADH + NH₄⁺
2) Transamination via AST to produce aspartate
Glutamate + oxaloacetate -> aspartate + α-ketoglutarate
Both NH₄⁺ and aspartate can then join into the urea cycle
Therefore, genetic defects in urea cycle -> hyperammonaemia, mental retardation
Ammonia metabolism in liver
Most NH₄⁺ is processed in perportal cells, to become urea
Some NH₄⁺ escapes processing and so perivenous cells are efficient back up mechanism to convert to glutamine
Glutamine metabolism
In kidneys
Glutamine from perivenous cells in liver will be converted back to NH₄⁺ and HCO₃⁻ via glutaminase
Then all NH₄⁺ will be converted to urea and lost to urine
Glutaminase has two isoenzymes in liver and kidneys, subject to different regulation
The liver glutaminase produces an allosteric activator of CPS enzyme in urea cycle, N-acetylglutamate
Role of liver in pH homeostasis
Urea synthesis inhibited by acidosis - as urea synthesis consumes bicarbonate and produces H⁺, so inhibition acts to increase pH
Glutamine synthesis is stimulated by acidosis, so increases NH₄⁺ use, detoxifying
Glutaminase regulation by pH
Liver glutaminase is inhibited by acidosis, so decreasing the production of the allosteric activator of urea cycle
Kidney glutaminase is activated by acidosis, so increasing glutamine breakdown and release of NH₄⁺, and increasing HCO₃⁻, so increasing pH
Haem breakdown in liver
Red blood cells taken up by reticuloendothelial system at end of lifespan and broken down
Released Hb is broken down to amino acids + free iron + haem group
Bilirubin metabolism in liver
Haem group then converted to bilirubin, which binds to albumin as UNCONJUGATED BILIRUBIN
This then taken up by liver and conjugated in SER to polar group to make it water soluble -> CONJUGATED BILIRUBIN. This is catalysed by UDP glucuronyl transferase
Conjugated bilirubin then excreted in bile
or converted to urobilinogen in gut and excreted from gut
Hepatic jaundice
Bilirubin is yellow, so discoloration of skin and sclera of eyes in hyperbilirubinaemia
Result of decreased uptake, decreased conjugation and decreased transfer of conjugated bilirubin to bile
Increases blood conjugated and unconjugated bilirubin
Increases urinary conjugated bilirubin
Increases urinary urobilinogen
Decreased faecal urobilinogen
Post-hepatic jaundice
Caused by obstruction of biliary system - gallstones, cancer of head of pancreas, primary biliary cirrhosis
Increases blood conjugated bilirubin
Increases urinary conjugated bilirubin
No urinary or faecal urobilinogen
Pre-hepatic jaundice
When greatly increased haem breakdown - caused by trauma, haemolysis, thalassemia - so increased bilirubin supply to gut
Increases blood unconjugated bilirubin
Increases urinary urobilinogen
Increased faecal urobilinogen
Neonatal jaundice
Common, in 60% newborns
Build up of bilirubin due to low UDP glucuronyl transferase activity
Treated with blue fluorescent light to convert bilirubin to soluble form that can be excreted
In excess -> in brain, toxic encephalopathy, kernicterus -> brain damage
Increased blood unconjugated bilirubin
No urinary or faecal urobilinogen
Types of gallstones
Cholesterol stones - crystallised cholesterol, due to imbalance in bile components
Mixed stones - crystallised cholesterol precipitated with bile pigments
Pigment stones - calcium bilirubinate, due to deconjugation of bilirubin mono- and di- glucoronides
Risk factors for gallstones
Fair Fat Female Fertile Forty (+)
Rapid weight loss or gain
Diabetes
Gallbladder
40-50ml capacity
but liver secretes 600ml daily - concentrates bile 5-10x
Symptoms of gallstones
(15% of population have, 80% of these asymptomatic)
Biliary colic - spasm of gallbladder wall to try to shift lodged stone in neck of cystic duct
Acute cholecystitis - in prolonged impaction -> inflammation of gallbladder -> overgrowth of bacteria, infection
Chronic cholecystitis - repeated episodes of acute inflammation -> fibrosis and thickening of gallbladder wall, chronically colonised bile
Types of biliary obstruction
Anatomical:
Intraluminal - in tube (stones, polyps)
Mural - abnormal wall (tumour, stricture, scarring)
Extramural - outside pressing in (nodes, pseudocyst)
Disease:
Benign or malignant
Symptoms of biliary obstruction
Icterus (jaundice) - clearest in sclera, under tongue, nail beds, soles of feet
Pale floaty stools, dark urine
Pruritis - itching
Benign causes of biliary obstruction and extra symptoms
Stones
Pancreatitis
- painful
- fever, rigors
- tenderness
- impalpable gallbladder
Malignant causes of biliary obstruction and extra symptoms
Pancreatic adenocarcinoma
Cholangiocarcinoma (cancer of ducts)
Malignant porta hepatis lymph nodes
- painless
- palpable gallbladder
Investigations into biliary obstruction
ULTRASOUND
- look for intrahepatic duct dilation, duct stones, gallstones, mass
CHOLANGIOGRAPHY
- Endoscopic Retrograde Cholangio(Pancreato)graphy
= ERCP - camera into duodenum, inject dye to papilla
-percutaeous, intraoperative, magnetic resonance cholangiography - invasive so not 1st line
CROSS SECTIONAL IMAGING
CT usually, then MRI to look for masses (CT won’t show gallstones)
Biliary obstruction therapy
ENDOSCOPIC (ERCP) Sphincterotomy/stone retrieval Stent/dilatation PERCUTANEOUS (through liver) Stent/dilatation SURGERY Bile duct exploration Tumour resection Bypass (loop of SI attached to bile duct higher up to avoid blockage, give longer lasting relief)
Acute pancreatitis definition and causes
= acute inflammation of the pancreas associated with pancreatic duct obstruction and autodigestion
- gallstones
- alcohol
- idiopathic
- autoimmune, familial, viruses, ERCP complication
Symptoms of acute pancreatitis
Severe abdominal pain Increased serum amylase and lipase Ileus (gut slows peristalsis) Vomiting Tenderness Fever Tachypnoea Tachycardia Jaundice (if stone still present) Intravascular hypovolaemia
Chronic pancreatitis
= chronic inflammation and fibrosis, destruction of tissue and architectural changes
Progressive, continues even if remove causative factor
Endocrine and exocrine insufficiency
Increased risk of malignancy
Increased risk of pseudoaneurysm, bleeding
Causes of chronic pancreatitis
Alcohol Idiopathic Familial Hypercalcaemia Autoimmune
Morbidity triad of GI infection
Diarrhoea malnutrition infection
Increase in GI infections due to
Intensive farming Global distribution Mass production New microbes Convenience food Antibiotic use on farm animals -> resistance
Functions of gut flora
METABOLIC
- fermentation of non-digestible dietary residue and gut mucus
- salvages energy as short-chain fatty acids
- produce vitamin K
TROPHIC (nutrition)
- control of epithelial cell proliferation and differentiation
- development and maintenance of immune system
PROTECTIVE
- against pathogens, barrier effect
Normal colonisers of GI tract
Many in mouth
Fewer in stomach due to acidic environment
Mainly anaerobes in small and large intestines
Peridontal disease
Streptococcus mutans
Streptococci (gram +ve)
Actinomycetes
Anaerobic gram -ve
Peptic ulcer disease and stomach cancer
Helicobacter pylori
Predisposing factors for GI infections
Newborn infants - don't have developed protective flora Malnutrition Contaminated food/water Antibiotic use - suppresses normal flora Hypo/achlorhydria - lacking stomach acid Immunodeficiency
Causative agents of gastroenteritis
Viral - rotavirus, noravirus, adenovirus
Bacterial - campylobacter, E coli, shigella, salmonella, vibrio cholerae
Parasitic - giardia lamblia
Mechanisms of gastroenteritis
TOXINS - enterotoxins (V. cholerae, S. aureus) -> secretory diarrhoea, opens channels.
- cytotoxins (Shigella, E. coli 0157, C. diff) -> inflammatory diarrhoea, damages lining
ATTACHMENT - inhibiting absorption/secretion
DIRECT INVASION
IMPAIRED REABSORPTION
Non-inflammatory GI infection
Enterotoxin or adherence mechanism
See nothing on colonoscopy
V. cholerae, viruses, food poisoning
-> secretory diarrhoea
Inflammatory GI infection
Invasion or cytotoxin mechanism
See inflammation on colonoscopy
Campylobacter jejuni, Salmonella enteritidis, Clostridium difficile
-> inflammatory diarrhoea
Penetrating GI infection
See bacteraemia (bacteria in blood) Salmonella typhi, Yersinia enterocolitica
Complications of gastroenteritis
Dehydration, shock, MOF (multiple organ failure), death
Electrolyte disturbances - hypokalaemia, acidosis
Sepsis
Toxic megacolon
Perforation
Ileus -> obstruction
Intussusception
Delayed complications of gastroenteritis
Reactive arthritis Guillan-Barre syndrome Transverse myelitis Haemolytic Uraemic Syndrome Chronic fatigue Irritable bowel syndrome Inflammatory bowel disease
Types of Escherichia coli
ENTEROTOXIGENIC E.COLI
- cause of infant diarrhoea, traveller’s diarrhoea
- self limiting
ENTEROPATHOGENIC
- diarrhoea in tropics, rarely developed world
- self limiting
ENTEROHAEMMORHAGIC
- eg 0157 E.coli
- zoonotic, usually after eating meat
can -> HUS - micro-angiopathic anaemia, acute renal failure, thrombocyopenia
Food poisoning
Toxin- mediated, quick onset as no need for bacterial multiplication
Vomiting, sometimes also diarrhoea
Presentation of ulcerative colitis
Bloody diarrhoea (3+ loose or liquid stools per day (200g+))
No pain
May be acute and severe
Prolonged
Possible joint, skin, mouth symptoms also
Fever/tachycardia Anaemia Clubbing Abdominal tenderness ---> possible, may look well
Investigations for UC
If acute (less than 4 weeks), consider infection (travel), drugs eg ibuprofen
Blood test - anaemia, inflammatory markers
Sigmoid/colonoscopy - loss of surface layer, obvious mucus and blood
Histology - glandular distortion, inflammation, crypt abscesses
Epidemiology of UC
Usually begins in young adults Men and women equally affected Higher risk in UK than SE asia 15% have 1st degree relative with IBD 3x more common in non-smokers Appendectomy decreases risk
Disease course of UC
Usually intermittent (75% do well), but some frequently relapse, some chronic continuous Usually returns less severe, and then becomes more severe as spreads up
Categorisation of UC
SEVERE UC
6+ stools daily, bloody stools, fever, tachycardia, anaemia
(mortality risk!!)
MODERATE UC
4+ stools daily, minimal systemic effects
MILD UC
<4 stools daily, no systemic disturbance
Treatment for UC
Steroids - 80% respond well, but many side effects
Ciclosporin - cytotoxic agent CiA - bridge drug, not forever - immunosuppressant
Infliximab - biologic agent
Surgery - colectomy (remove all colon, risky), stoma (ileostomy bag), ileoanal pouch (artificial rectum, storage space and some control, but still 6-8 stools per day, risk of malignancy at anal margin)
5-ASA/Azathioprine - for long term maintenance - orally or enema/suppositories
Combination therapy best!
Children with IBD
Possible!
Tends to be very severe
Have to medicate off-license, as most medications limited to adults
Risk of colorectal cancer in UC
The more severe, extensive and long-lasting the UC, the higher risk of CRC
7-30% will get, so some opt for colectomy
Do surveillance colonoscopy to look for early signs of cancer 10 years after UC diagnosis, then repeat according to risk
Drug in body ->
Drug -> inactive metabolites
Drug -> active metabolites
Drug -> toxic metabolites
Prodrug -> drug (improved selectivity)
Hepatic drug metabolism
Drug –phase I–> derivative –phase II–> conjugate
Drug more lipid soluble, conjugate less, so drug will be reabsorbed in distal tubule
Most drugs metabolised by more than one phase I or II pathway, so produce multiple metabolites
Phase I
- in ER
- derivative formed by oxidation, reduction or hydrolysis
- introduces or exposes a reactive site on drug molecule
Phase II
- in cytosol
- conjugation of species formed in phase I with polar molecules, so less lipid soluble, so easier to excrete in urine
Factors affecting drug metabolism
Enzyme induction Enzyme inhibition Genetic polymorphisms Disease Age
Enzyme induction affecting drug metabolism
Some drugs increase expression of cytochrome p450 enzymes
Can cause failure of other drugs to produce significant therapeutic effects
Can also be autoinductors
Half life decreases
Time to steady state decreases
Steady state Css decreases
Enzyme inhibition affecting drug metabolism
Directly inhibit p450 enzymes Can increase adverse effects and toxicity in patients Half life increases Time to steady state increases Steady state Css increases
Genetic polymorphisms affecting drug metabolism
Poor ability to metabolise drugs by some groups
If all given same initial dose and Cp measured 6 hours later, have different responses.
Fast acetylators
Slow acetylators - mutation in phase II enzymes
Can also influence therapeutic effects of prodrugs
Increase or decrease activity of metabolising enzymes
Disease affecting drug metabolism
Disease in liver function affects drugs metabolised in liver
Disease in renal function affects drugs excreted unchanged in urine
Disease in thyroid function affects liver metabolising enzymes (increased thyroid function increases metabolic rate)
Disease in cardiovascular system affects rate of delivery of drug to liver/kidney
This may influence drug treatment - digoxin is excreted unchanged in urine, but in renal disease increased half life increases toxicity, so give digitoxin instead which is metabolised in liver
Age affecting drug metabolism
Decreased drug metabolism in the very young and the elderly, as less efficient kidneys and liver, more likely to get adverse effects
Metabolism of paracetamol
Usually by 2 phase II reactions
- But prolonged use saturates the phase II conjugating enzymes
- Drug now metabolised by phase I to a toxic intermediate NAPQI
- NAPQI can still be conjugated with glutathione, but when this is depleted, it reacts with cell proteins to cause hepatic cell damage – fatal
Treat with activated charcoal if within 24 hours of ingestion
More effective if given sooner
Hepatitis A
- transmitted faeco-orally or from close personal contact, travel virus
- acute infection for ~6 months, not chronic
- preventable by pre/post exposure immunisation
Vaccinated if:
> travelling outside europe, north america, australasia
> close contact with someone with hep A/exposure at work
> chronic liver disease
> injecting drug user
> blood clotting problems
> MSM
HAV-IgM in serum - acute infection
HAV-IgG in serum - past infection
Types of hepatitis B
Chronic persistent hepatitis - asymptomatic
Chronic active hepatitis - symptomatic exacerbations
Cirrhosis of liver
Hepatocellular carcinoma
- 90% children will get chronic infection
- 95% adults will clear virus
Progression of hepatitis B
Acute -> inactive hepatitis -> hepatitis -40 years on-> cirrhosis -> liver cancer
HBsAg peaks, then IgM anti-HBc, then IgM anti-HBs
HBeAg - transmissable
HBeAb - low transmissability
Epidemiology of hepatitis B
Primary infection route mother-child, many countries vaccinate at birth
30%+ of the world has been infected
25% will go on to develop serious liver disease
75% of all primary hepatocellular carcinoma occurs in HBV carriers
Modes of transmission of hepatitis B
Most contractable from blood, serum, wound exudates. Also slightly from semen, vaginal fluid, saliva.
Sexual - MSM and sex workers at risk
Parenteral - health workers
Perinatal - mother to child
Treatment of hepatitis B
Interferon
Lamivudine
- if successful, no HBsAg or HBV-DNA, and increase in HBeAg
Prevention of hepatitis B
Vaccination - very effective, given to those at increased risk. Routinely to neonates in some countries
Hepatitis B immunoglobulin - HBIG protects those exposed to hep B if given within 48 hours
Hepatitis C
~20% will get acute hepatitis -> recover
~80% will get chronic hepatitis -> 3% get hepatocellular carcinoma
Symptoms begin like a mild viral infection, then -> chronic persistant hepatitis -> chronic active hepatitis -40 years on-> cirrhosis -> liver cancer
Leading cause for liver transplant worldwide
Risk factors for hepatitis C
Transfusion/transplant from infected donor
Injecting drug use
Haemodialysis
Accidental sharps injuries
Sexual or household exposure to anti HCV positive contact
Multiple sexual partners
Birth from an infected mother
Types of HCV
6 major types
Prevalence of each different in different countries
Cause different kinds of diseases, and respond differently to treatment
Most research done in those prevalent in developed world
Diagnosing hepatitis C
HCV antibody - only after the acute phase, takes 4 weeks+ for antibody to appear
HCV RNA - via PCR - can diagnose in early phase, but mainly to monitor response to antiviral therapy
HCV antigen - via ELISA, as above but easier to carry out
Prevention of hepatitis C
Screen and test donors
Virus inactivation of plasma-derived products
Risk reduction counselling
Infection control
Hepatitis E
= Calicivirus
Acute, self limiting
Mortality of 40%, fulminant liver failure in pregnant women
Via gross faecal contamination of drinking water
Liver function test
Bilirubin Enzymes - aminotransferases AST and ALT, and alkaline phosphatase Albumin Total protein Globulins
γGT (gamma glutamyl transferase)
Clotting (prothrombin time) - marker of liver synthetic function
- these two are extras, can be requested
Liver enzymes
ALT - alanine aminotransferase - in very small amounts elsewhere
AST - aspartate aminotransferase - also elsewhere
ALP - alkaline phosphatase - also in bone and placenta
γGT - gamma glutamyl transferase - specific to liver, but not to types of liver disease (tells us if disease in liver or not)
ALP increases in cholestatic liver disease
ALT increases in hepatocellular liver disease
AST/ALT ratio
AST is raised in other conditions
ALT is specific to liver
AST/ALT ratio more than 1 - alcoholic liver damage
AST/ALT ratio less than 1 - non-alcoholic liver damage (BMI over 30)
Unconjugated vs conjugated bilirubin
UNCONJUGATED
Insoluble in water
Not in urine
Prehepatic or hepatic jaundice if present
CONJUGATED
Soluble in water
In urine
Hepatic or post hepatic jaundice if present
Liver turns unconjugated to conjugated
Gut turns conjugated to urobilinogen
Liver disease affecting drug metabolism
Cirrhosis decreases phase I metabolism, has no effect on phase II metabolism
Acute alcohol exposure decreases rate of both phase I and II metabolism
Chronic alcohol exposure to a healthy liver increases the drug metabolising activity
Chronic alcohol exposure to a pathological liver decreases phase I metabolism
Pituitary, thyroid and pancreas affecting hepatic drug metabolism
Pituitary gland - growth hormone inhibits hepatic drug metabolism, particularly in children
Thyroid gland - thyroid hormones induce hepatic drug metabolism (normal = euthyroid)
Pancreas - insulin induces hepatic drug metabolism
