Physiology 2.0 Flashcards
Lecture 1 = Physiology & Pharmacology of the LARGE INTESTINE
Lecture 1 = Physiology & Pharmacology of the LARGE INTESTINE
how long is the large intestine approximately?
1.7m long, average 6cm in diameter
what 4 things does the large intestine comprise?
1) caecum & appendix
2) colon
3) rectum
4) anal canal & anus
what are the 4 parts to the colon?
- ascending
- transverse
- descending
- sigmoid
what is the longitudinal smooth muscle in caecum and colon divided into?
= 3 strands called taeniae coli.
what do the 3 strands; taeniae coli encircle?
= the rectum and anal canal
when is the smooth muscle of he colon and caecum thickened?
= a he internal anal sphincter
what is the internal anal sphincter surrounded by?
- skeletal muscle of external anal sphincter
what does activity of taeniae coli and circular muscle layers in colon cause?
= ‘sac-like’ bulges = the hausfrau
- that very slowly change location
Yes or No.
Does the caecum and appendix have specialised functions in humans?
= No.
how much material, e.g. indigestible residues, un-absorbable biliary components, unabsorbed fluid, does the caecum normally receive?
1.0 - 2.0L per day
where does the caecum receive these materials from?
the terminal ileum
how is entry from terminal ileum to caecum permitted?
by gastro-ideal reflex in response to gastrin and CCK through the ‘one-way’ ileocaecal valve.
how does the ileocaecal valve act?
- maintaining + resting pressure
- relaxing in response to distension of duodenum
- contraction in response to distension of ascending colon
- being under control of vagus nerve, sympathetic nerves, enteric neurones and hormonal signals
what is the appendix?
= a blind ended tube with extensive lymphoid tissue connected to distal caecum via the appendiceal orifice
how can appendicitis arise?
= through obstruction of appendices by a faecalith
what are the 4 functions of the colon?
1) absorption
2) secretion
3) reservoir
4) periodic elimination of faeces
describe what the colon absorbs and why they absorb this?
1) Na+, Cl- and H20
- to condense ileocaecal material to solid, or semi-solid, stool
2) short chain fatty acids
- carbohydrates not absorbed by small intestine is fermented any colonic flora to short chain fatty acids
what does the colon secrete and keep for a reservoir?
Secretes = K+, HCO3- and mucus
Reservoir = storage of colonic contents
what are faeces composed of?
(150g of faeces a day)
- 100g H20
- 50g solid including cellulose, bacteria, billirubin, small amount of salt
what does the mucosa of colon lack and posses?
Lacks = villi
Possesses; = colonic folds = crypts = microvilli - that increase the surface area
what mediates electrolyte absorption in the colon?
= surface epithelial cells (colonocytes) mediate electrolyte absorption which by osmosis, drives absorption of H20
what do crypt cells mediate?
= ion secretion
what do goblet cells secrete?
= copious mucus containing glucosaminoglycans - hydrated to form a slippery surface gel
= trefoil proteins involved in host defence
what does trans-epithelial movement of electrolytes involve?
= numerous transporters & ion channels
what is Na+ absorption & K+ secretion enhanced by?
when can a significant amount of K+ be lost in the faeces?
= aldosterone
K+ lost
= in secretory diarrhhoea
if 1-2L of ileacocael material enters the colon per day, how much of it is absorbed?
= 0.1L
- colon capable of substantially greater absorption of material
what is haustration?
(a pattern of motility in large intestine)
= non-propulsive segmentation
what is peristaltic propulsive movements?
(a pattern of motility in large intestine)
= mass movement
what is defaecation?
(pattern of motility in large intestine)
= periodic egestion
describe what happens in haustration.
- Hastrua = are saccules caused by alternating contractions of circular muscle
(similar to segmentation, but much lower frequency)
= disappear before and reappear after mass movement
= probably generated by slow wave activity
= mixes content - allowing time for fluid and electrolyte re-absoprtion
what is mass movement?
= simultaneous contraction of large sections of circular muscle of ascending and transverse colon, powerfully driving faeces into distal regions.
how often does mass movement occur?
1-3 times a day
when is mass movement triggered?
= by a meal (often breakfast) via gastrocolic response involving;
- gastrin
- extrinsic nerve plexuses
what does mass movement in distal colon result in?
= propulsion of faeces into rectum, triggering defection reflex in response to rectal stretch
in defaecation, describe the stepwise progression that happens after mass movement which causes the rectum to fill with faecal matter.
1) activation of rectal stretch receptors
2) contraction of Smooth muscle of sigmoid colon and rectum
- internal anal sphincter relaxes
CAN NOW GO TWO WAYS:
- relaxation of skeletal muscle of external anal sphincter
(defaecation assisted straightening of anorectal angle, abdomen skeletal muscle contraction and expiration against closed glottis)
- contraction of skeletal muscle of external anal sphincter
(defaecation delayed = rectal wall gradually relaxes)
describe what 2 ways the activation of rectal stretch receptors could go?
1) activation of afferents to spinal cord
- activates parasympathetic efferents
2) activation of afferents to brain (urge to defaecate)
- altered firing in efferents to spinal cord
describe the colons bacterial content?
= contains 10 times more bacteria than entire human body
- 500-1000 different species, most of which re beneficial and are commensals
what do colons’ bacteria do?
- increase intestinal immunity by competition with pathogenic microbes
- promote motility & help maintain mucosal integrity
- synthesise Vit K2 and free fatty acids (from carbohydrates) that are absorbed
- activate some drugs (e.g. used in treatment of IBD)
what else permits expulsion of intestinal gas (flatus) as well as faeces?
anus
how do gases arise? (3)
- swallowed air (most ‘burped’ up - eructation) but some enters small intestine but is either absorbed or passed to colon
- bacteria in colon which attack forms of carbohydrate that are indigestible to humans
- gas not absorbed by large intestine is expelled through anus = selective expulsion requires abdominal contractions; internal and external sphincters are contracted to form an ‘exit’ too narrow for solid matter to escape
what is constipation?
= presence of hard dried faeces within the colon (resulting from delay in defaecation and enhanced absorption of H20)
what are 5 possible causes of cosntipatioin?
- ignoring, or suppressing, the urge to defaecate
- decreased colonic motility (e.g. improper diet, drugs, metabolic disorder, old age)
- obstruction of faecal movement
- paralytic ileum following abdominal surgery
- impaired motility/defaecation reflex (e.g. Hirschprung reflex, involving absence of a section of ENS)
what are symptoms of constipation?
- abdominal discomfort
- headache
- loss of appetite
- general Malaise
= caused by prolonged distension of large intestine NOT toxins absorbed from retained faecal matter (given normal liver)
what is another cause of appendicitis?
= appendicoliths
- hardened, calcified, faecal matter within the appendix
what are laxatives?
= agents used to treat constipation
what are purgatives?
= agents cause purging, or cleansing, of the bowels by promoting evacuation
when should neither laxatives or purgatives never be used?
= never used when there is a physical obstruction to the bowel
what do laxatives increase?
= peristalsis and/or soften faeces causing, or assisting, evacuation
what are 2 problems with laxatives?
1) can be abused in eating disorders and also disguise underlying disease
2) are used too readily in some people
- leading to laxative dependency due to development of atonic colon
what are 3 medically sound uses of laxatives/purgatives?
1) when straining is potentially damaging to health (e.g. patients with angina), or when defaecatioin is painful (e.g. haemorrhoids) predisposing to constipation
2) to purge the bowel before surgery, or endoscopy
3) to treat drug induced constipation, or constipation in bedridden or elderly patients
what are 4 types of laxatives/[urgatiives?
1) Bulk laxativies
2) Osmotic laxatives
3) stimulant puurgatives
4) faecal softernes
what are bulk laxatives and how do they work?
give an example of them.
They are = indigestible polysaccharide polymers
Work by = improve stool consistency, slow acting
e.g. methycellulose = orally
what are osmotic laxative and how do they work?
give an example.
They are = poorly absorbed solutes
Work by = acting rapidly
e.g. magnesium sulfate or hydroxide = orally
Sodium citrate = rectally
Lactulose = orally
describe faecal softness?
= detergent like action
(e. g. decussate sodium = rally)
- arachis oil as enema
- oral liquid paraffin used In past
describe stimulant purgatiives.
(e. g. bisacodyl = orally, or suppository when rapidly acting)
- Sodium picosulfate is similarly acting
- Senna is an anthraquinone laxative
what are 2 things in the category for chronic bowler disease?
1) irritable bowel syndrome (IBS)
2) inflammatory bowel disease (IBD)
what are symptoms of IBS and how would you treat it?
= as bouts of diarrhoea, constipation, or abdominal pain
treatment;
- symptomatic with adjustments of diet and anti-diarrhoeals, anti-spasmodics or laxatives as required.
what might IBD affect?
= the entire gut (Crohn’s disease) or colon (ulcerative colitis)
how would you treat IBD?
1) glucocorticoids
= for acute attacks
e.g. prednisolone, budesonide
- but prolonged use limited by adrenal suppression
2) amiiinosalicylates
= useful for ulcerative colitis, for maintenance and mild disease
what are 3 example fo aminosalicylates used to treat chronic bowel disease, specially IBD.
1) Sulfasalazine – 5-aminosalicylic acid (5-ASA, active moiety) linked to sulfapyridine (associated with adverse effects). 5-ASA released by colonic bacteria
2) Mesalazine – preparation that releases 5-ASA in the colon
3) Olsalazine – 5-ASA dimer linked by an azo bond cleaved by colonic bacteria. Balsalazide (a prodrug) also yields 5-ASA following cleavage
Lecture 2 = Physiology & Pharmacology
- NAUSEA AND EMESIS
Lecture 2 = Physiology & Pharmacology
- NAUSEA AND EMESIS
what is nausea?
= subjective, highly unpleasant sensation
- normally felt in throat & stomach as a ‘sinking’ sensation
describe acute and chronic nausea?
Acute
- interferes with mental and physical activity
- often relieved by vomiting
Chronic
- greatly debilitating
what are symptoms of nausea?
- pallor
- sweating
- excessive salivation
what does nausea involve?
= relaxation of stomach and lower oesophagus
= upper intestinal contractions, forcing intestinal contents by reverse peristalsis into stomach h
what does nausea usually precede?
= vomiting, but either may occur in isolation
what does retching involve?
= rhythmic reverse peristalsis of stomach and oesophagus
= forceful, involuntary, contraction of abdominal muscle and diaphragm - cardiac portion of stomach pushed into thorax
= upper intestinal contractions, forcing intestinal contents by reverse peristalsis into stomach
what are symptoms of retching?
- pallor
- sweating
- excessive salivation
- no efflux of vomitus
what is vomiting (emesis)?
= forceful expulsion of gastric/intestinal contents out of the mouth
how does vomiting commence?
= commences with forceful inspiration, reflex closure of glottis and elevation of soft palate to close off airways and nasal passages.
= NOT due to stomach contraption, stomach, oesophagus and associated sphincters and relaxed.
how is vomiting co-ordinated by?
= vomiting centre (VC)
where is the vomiting centre located?
in medulla oblongata of brain stem
describe the 5 events in vomiting.
1) suspension of intestinal slow wave activity
2) retrograde contractions from ileum to stomach
3) suspension of breathing (closed glottis-preventing aspiration)
4) relaxation of LOS - contraction of diaphragm and abdominal muscles compressing stomach
5) ejection of gastric contents through UOS
what 2 things can start the pathway of stimulating vomiting off?
1) toxi materials in gut lumen
(e. g. bacterial toxins, salts of heavy metals, ethanol)
2) systemic toxins
(e. g. cytotoxic drugs)
what do the toxic material and systemic toxins stimulate?
= enterochromaffin cells in the mucosa
what mediators are released in the enterochromaffin cells in mucosa?
= 5-HT
what happens after stimulation of enterochromaffin cells in mucosa?
= depolarisation of sensory afferent terminals in mucosa (e.g. via 5-HT3 receptors)
= action potential discharge in vagal afferents to brainstem (CTZ and NTS)
= co-ordination of vomiting by the vomiting centre
what does absorbed toxic materials and drugs in blood stimulate?
= CTZ within AP of brainstem (lacks an effective blood bran barrier BBB)
what does mechanical stimuli (e.g. pharynx); pathology within GI tract (e.g. gastritis) or other visceral organs (MI) stimulate?
= vagal afferents to brainstem (CTZ and NTS)
what does vesicular system (Labyrinths)
e.g. motion sickness, Meniere’s disease signal thorough?
= vestibular nuclei
= CTZ
what does stimuli within the CNS (e.g. pain, repulsive sights and odours, fear, anticipation, physiological factors) signal through?
= cerebral cortex, limbic system
= medulla
where is motor output that co-ordinates vomiting located?
= in the brainstem
what is the vomiting centre?
= a group of inter-connected neurones within the medulla that are driven by a central pattern generated (CPG) that in turn receives input from NTS
what are 3 examples of vagal efferents?
- oesophagus (shortening)
- stomach (proximal relaxation)
- small intestine (giant retrograde contraction)
what are 2 examples of somatic motor neurones?
- anterior abdominal muscle (contraction)
- diaphragm (contraction)
what are 4 examples of autonomic/somatic efferents?
- heart (increasing rate, force)
- salivary glands (increasing secretion)
- skin (pallor, cold, sweating)
- sphincters of bladder and anus (constriction)
what are 5 consequences of severe vomiting?
- dehydration
- loss of gastric protons & Cl- ions (causing hypochloraemic metabolic alkalosis, raising blood pH)
- hypokalaemia
(mediated by kidney, proton loss accompanied by K+ excretion) - rarely, loss of duodenal bicarbonate may cause metabolic acidosis
- rarely, oesophageal tamale (Mallor-Weiss tear)
what are 6 example of drugs and radiation that induce emesis?
- cancer chemotherapy
e. g. cisplatin, doxorubicin and radiotherapy - operations involving administration of general anaesthetic (post-operative nausea and vomiting)
- agents with dopamine agonist properties (e.g. levodopa used in Parkinson’s disease)
- morphine and other opiate analgesics (tolerance develops)
- cardiac glycosides (e.g. digoxin)
- drugs enhancing 5-HTT function (e.g. SSRIs, 5-HT3 receptors are prevalent in CTZ)
what are the 6 major classes of anti-emetic drugs?
1) 5-HT3 receptor antagonists - ‘setrons’
2) muscarinic ACh receptor antagonists
3) Histamine H1 receptor antagonists
4) Dopamine receptor antagonists
5) NK1 receptor antagonists
6) cannabinoid (CB1) receptor agonist
give an example of 5-HT3 receptor antagonists.
what do these drugs do?
- ondansetron
- palonosetron
= suppress chemotherapy and radiation induced emesis and post operative nausea and vomiting
= block peripheral and central 5-HT3 receptors
describe the effect 5-HT3 receptor antagonists drugs have.
= reduce acute nausea, retching and vomiting in cancer patients receiving emetogenic treatments (Day 1)
= less effective during subsequent treatments - improved by addition of a corticosteroid and neurokinin (NK1) receptor antagonist
= NOT effective against motion sickness, or vomiting induced by agents increasing dopaminergic transmission
= well tolerated, may cause headaches and constipatiton
give an example of a muscarinic ACh receptor antagonist.
- Hyosine
- scopolamine
when are muscarinic ACh receptor antagonist used?
how do they act?
= for prophylaxis and treatment of motion sickness (delivered by transdermal patch)
- block muscarinic ACH receptors at multiple sites (e.g. vestibular nuclei, NTS, vomiting centre)
- directly inhibiting GI movement and relaxation of GI tract
what effect do muscarinic ACH receptor antagonists have?
- inhibition of GI movements and relaxation of GI tract may contribute to anti-emetic effects
= numerous unwanted effects resulting from blockage of parasympathetic ANS;
- blurred vision
- urinary retention
- drug mouth
- centrally mediated sedation
give examples of histamine H1 receptor antagonists.
- cyclizine
- cinnarizine
+ many others
NOTE = many agents in this class exert significant blockage of Muscarinic receptors probably contributing to their activity
what are histamine H1 receptor antagonists used fro?
= prophylaxis and treatment of motion sickness and acute labyrinthitis and nausea and vomiting caused by irritants in stomach
- less effect against substances that act directly on CTZ
= action attributed to blockage of H1 receptors in vestibular nuclei and NTS
what are the effects of Histamine H1 receptor antagonists?
- CNS depression and sedation
- drowsiness, affecting performance of skilled tasks
what are examples of dopamine receptor antagonists?
- domperidone
- metoclopramide
when are dopamine receptor antagonists used?
= for drug induced vomiting (e.g. cancer chemotherapy, treatment of Parkinson’s disease with agents stimulating dopaminergic transmission) and vomiting in GI disorders
- use in children is restricted
= not effective against motion sickness
how do dopamine receptor antagonists work?
- centrally block dopamine D2 (&D3) receptors in CTZ
- peripherally exert a pro kinetic action on oesophagus, stomach and intestine
describe domperidone and BBB?
= domperidone doesn’t cross the BBB and is less likely to result in many unwanted effects of metoclopramide
what are phenothiazines?
= owe part of their action to dopamine D2 blockade, and are used for severe nausea and vomiting
give an example of a NK1 receptor antagonists and describe when they are used?
= aprepitant
- used in combo with a 5-HT3 receptor antagonist and dexamethasone in acute phase of highly emetogenic chemotherapy
- in combo with dexamethasone in delayed phase
= exact site of action is uncertain, but antagonists of substance P (causes committing and released by vagal afferents) is assumed
give an example of a cannabinoid (CB1) receptor agonist?
= nabilone
when is cannabinoid (CB1) receptor agonists used?
- in patient setting for treatment of cytotoxic chemotherapy that is un-responsive to other anti-emetics
what effect does cannabinoid (CB1) receptor agonists have?
- decrease vomiting induced by agents stimulating CTZ
= opiate receptors are involved in drug effect
= numerous unwanted side effects;
- drowsiness, dizziness, dry mouth, mode changes
Lecture 3 = Water balance in GI tract
Lecture 3 = Water balance in GI tract
Yes or No.
Absorption of water is a passive process?
= Yes.
How is the absorption of water driven?
= by the transport of solutes (particularly) Na+ from lumen of intestines to bloodstream
what is water ingested and secreted normally in balance with?
= water absorbed
Describe the amount of fluid entering tract per day, amount of fluid absorbed by small intestine and amount of fluid entering large intestine
= 9.3L entering tract per day
= 8.3L absorbed by small intestine
= 1L entering large intestine, of which 90% is absorbed
what is diarrhoea?
= a loss of fluid and solutes form GI tract in excess of 500ml per day
what is intestinal fluid movement always coupled to?
= solute movement
what are the 2 mechanisms of water movement?
1) transcellular routes
2) paracellular routes
what does the re-absorption of Na+ provide?
= provides a (local) osmotic force for re-absorption of water
what are the 5 principle mechanisms for re-absorption of Na+?
1) Na+/glucose co-transport
2) Na+/amino acid co-transport
3) Na+/H+ exchange
4) Parallell Na+/H+ and Cl-/HCO3- exchange
5) epithelial Na+ channels (ENaC)
where does Na+/glucose co-transport and Na+/amino acid co-transport occur?
= occurs throughout small intestine and most important in post-prandial period
where does Na+/H+ exchange occur and how is it stimulated?
= in duodenum and jejunum = stimulated by luminal HCO3-
where does parallel Na+/H+ and Cl-/HCO3- exchange occur?
= in ileum and colon most important in inter-digestive period, doesn’t contribute greatly to post-prandial absorption
where do epithelial Na+ channels (ENaC) occur?
= in colon (distal specifically) and is regulated by aldosterone but NOT by cAMP or cGMP
what is Na+/glucose and Na+.amino acid co-transport the major mechanisms for?
what are they both examples of?
= post-prandial Na+ absorption in jejunum
- examples of secondary active transport and are electrogenic (as is the Na+/K+ ATPase = collectively overall transport of Na+ generates a trans-epithelial potential (VTE) in which the lumen is negative = driving parallel absorption of Cl-
describe Na+/glucose and Na+/amino acid co-transport regulation?
= neither are regulated by intra-cellular cAMP or Ca2+
describe where Na+/H+ exchange occurs?
- in jejunum at both apical and baso-lateral membranes
Apical
= NHE2 and NHE3
Baso-lateral
= NHE1
thinking about where Na+/H+ exchange occurs, where is the only places to contribute to trans-epithelial movement of NA+ (and regulation of intracellular pH) and the place that is a cellular pH housekeeper?
Only place contributing to trans-epithelial movement of Na+
= NHE2 and NHE3
Cellular pH housekeeper
= NHE1
in Na+/H+ exchange, what is exchange at apical membrane in jejunum stimulated by?
= by alkaline environment of lumen (i.e. high pH = low proton concentration) due to presence of bicarbonate from pancreas
describe absorption and regulation in Na+/H+ and Cl-/HCO3- exchange in parallel involved in Na+ absorption.
Absorption = electro-neutral
Regulated = by cAMP, cGMP, Ca2+ which all reduce NaCl absorption
- reduction in NaCl absorption is a cause of diarrhoea (e.g. secretory diarrhoea due to infection with E. coli = heat stable enterotoxin from which activates adenylate cyclase and increases intracellular cAMP)
what do epithelial Na+ channels mediate in Na+ absorption?
= mediate electrogenic Na+ absorption in distal colon
- highly efficient and important in Na+ conservation
what are the 3 actions of aldosterone in epithelial Na+ channels involved in Na+ absorption?
1) opens ENaC = seconds
2) inserts more ENaC into membrane from intracellular vesicle pool = minutes
3) increases synthesis of ENaC and Na+/K+-ATPase = hours
describe how Cl- absorption can occur?
= passively via transcellular or paracellular routes
describe what happens in small and large intestine during Cl- absorption.
In small intestine
= driving force provide by lumen negative potential due to electrogenic transport of Na+ (Na+/glucose and Na+/amino acids)
In large intestine
= driving force provided by lumen negative potential due to electrogenic movement of Na+ through ENaC
what are 2 other mechanisms of Cl- absorption?
1) Cl–HCO3- exchange (ileum, proximal and distal colon)
2) parallel Na+/H+ and Cl-/HCO3- exchange (ileum and proximal colon)
describe the rate of which Cl- secretion occurs at?
= basal rate, but is usually overshadowed by a higher rate of absorption
what cells does Cl- secretion occur from?
= occurs from crypt cells, rather than villus cells.
what are 3 processes involved in Cl- secretion in the baso-lateral membrane?
1) Na+/K+ ATPase
2) Na+/K+/2Cl- co-transporter (NKCC1)
3) K+ channels (IK1 and BK)
what drives the inward movement of K+, Na+ and Cl- via NKCC1 in Cl- secretion?
= low intracellular Na+
describe what happens to intracellular concentrations of Cl- when K+ is recycled via K+ channels?
intracellular concentrations of Cl- increase providing an electrochemical gradient for Cl- to exit the cells via CFTR on apical membrane
what provides voltage dependent secretions of Na+ through paracellular pathway in Cl- secretions?
= lumen negative portenial
why are there usually little secretions of Cl-?
= because apical CFTR is either closed, or not present
when do secretions occur?
= when CFTR is indirectly activated by;
1) bacterial enterotoxins [e.g. cholera toxin (V. cholerae), heat stable enterotoxin (E. coli), C. difficile toxin]
2) hormones and neurotransmitters [e.g. vasoactive intestinal peptide (VIP), guanylin, acetylcholine, bradykinin, 5-HT (serotonin)]
3) immune cells products (e.g. prostaglandins*, histamine)
4) some laxatives (e.g. bile acids)
how else can CFTR be activated by?
= as a result of generation of second messengers including;
- cAMP (e.g. cholera toxin, VIP, histamine)
- cGMP (e.g. heat stable enterotoxin, guanylin)
- Ca2+ (e.g. acetylcholine, bradykinin, 5-HT
what does Cl- conductance, mediated by CFTR result from?
- opening of channels at apical membrane
- insertion of channels from intracellular vesicles into the membrane
what are 5 causes of diarrhoea?
- infectious agents
= viruses, bacteria (traveller’s diarrhoea) - chronic disease
- toxins
- drugs
- psychological factors
what can diarrhoea involve in terms of location?
= small, or large, intestine
what can diarrhoea result in?
= dehydration (Na+ and H20 loss) = metabolic acidosis (HCo3- loss) = hypokalaemia (K+ loss) = can be fatal if severe (cholera)
what are 3 treatment options for severe acute diarrhoea?
1) maintaining fluid & electrolyte balance
2) use anti-infective agents
3) use non-antimicrobial anti-diarrhoeal agents (symptomatic)
what are 4 causes of diarrhoea?
1) impaired NaCl absorption
2) excessive secretion
3) hyper-motility
4) non-absorbable, or poorly absorbable, solutes in intestinal lumen
give 4 possible causes of impaired absorption of NaCl which could cause diarrhoea.
- congenital defects
e. g. congenital chloridorrhoea, absence of Cl–HCO3- exchanger - inflammation
- infection
e. g. enterotoxins from strains of E.coli and campylobacter sp. - excess bile acid in colon
give an example of non-absorbable or poorly absorbable solutes in intestinal lumen which could cause diarrhoea?
= lactase deficiency
what is a classic example of excessive secretion which could cause diarrhoea?
- cholera
= cholera toxin (CTX) enters enterocyte
= enzymatically inhibits GTPase activity of the Gs subunit
= increased activity of adenylate cyclase
= increased concentration of cAMP
= cAMP stimulates CFTR
= hypersecretion of Cl-, with Na+ and water following
what does rehydration therapy exploit?
= SGLT1
how does rehydration therapy exploiting SGLT1 work?
1) 2Na+ bind
2) affinity for glucose increases, glucose binds
3) Na+ and glucose translocates from extracellular to intracellular
4) 2Na+ dissociate, affinity for glucose falls
5) glucose dissociates
6) cycle is repeated
what 4 things do oral rehydration salts contain?
- glucose, 20g
- sodium chloride, 3.5g
- sodium bicarbonate, 2.5g
- potassium chloride, 1.5g
= dissolved in a volume of 1L dinking water
what does absorption of Na+ and glucose by SGLT1 cause accompanied absorption of?
= water
what type of drugs have anti-diarrhoeal activity?
= morphine like (or opioid) drugs
what are the actions of opioids on the alimentary tract?
- inhibition of enteric neurones (hyper polarisation via activation of U-opioid receptor)
- decreased peristalsis, increased segmentation (i.e. constipation)
- increased fluid absorption
- constriction of pyloric, ileocaecal and anal sphincter
- increased tone of large intestine
what are the 3 major opioid agonists used in diarrhoea and describe them briefly?
1) codeine
2) diphenoxylate
- low CNS penetration, low solubility in water (decreased abuse potential), many preparations contain atropine
3) loperamide
- low CNS penetration, low solubility in rate, undergoes enterohepatic recycling
Lecture 4 = Physiology and pharmacology of the LIVER
Lecture 4 = Physiology and pharmacology of the LIVER
what are the metabolic functions of the liver?
= regulation of carbohydrate, lipid and amino acid metabolism
1) carbohydrate metabolism (hormonally regulated)
2) fat metabolism (breakdown and synthesis)
3) protein metabolism
what 4 processes are involved in carbohydrate metabolism?
1) gluconeogenesis
produces glucose from amino acids
2) glycolysis = forming pyruvate then lactate (anaerobic conditions) or acetyl coA (aerobic conditions)
3) glycogenesis
= stored polymerised glucose, as glycogen
4) glycogenolysis
= releases glucose as required
what is involved in fat metabolism?
- processing of chylomicron remnants
- synthesis of lipoproteins (e.g. VLDLs, HHDLs; for export) and cholesterol (for steroid hormone & bile acid synthesis)
- ketogenesis (in starvation)
what 3 things are involved in protein metabolism?
- synthesis of plasma proteins
- transamination and deamination of amino acids
- conversion of ammonia to urea
what is the livers role in terms of hormones?
= many hormones are inactivated/degraded by liver;
DEACTIVATION
- insulin
- glucagon
- anti-diuretic hormone, ADH, vasopressin
- steroid hormone
ACTIVATION
- conversion of thyroid hormone (TH) [by deionisation of thyroxin (T4) to more active triiodothyronine (T3)]
- conversion of vit D to 25-hydroxyvitamin D2 (calcifediol) = future activation to 1,25-dihydroxyvitamin D3 (calcitriol) occuring in kidney
what 4 things does the liver store?
1) fat soluble vitamins, A, D, E, K (in hepatocytes)
2) water soluble vitamins B12 (hydroxycobalmin)
3) iron, copper
4) glycogen
what proteins does the liver synthesis?
- coagulation factors II, VII, IX and X (which requires post-translational modification by Vit K dependency gamma-carboxylation)
= also protein C and S - albumin
- complement poteins
- apolipoproteins
- carrier proteins
how does the liver act as a form of protection?
1) Kupffer cells (liver phagocytes)
= digest/destroy particulate matter, bacteria, and senescent erythrocytes
2) produce immune factors
= host defence proteins (acute phase proteins)
how does the liver act as a detoxifier?
= many endogenous substances (e.g. bilirubin as a metabolite of haemoglobin breakdown)
= exogenous substances (xenobiotics)
- drugs
- ethanol (alcohol)
what does bile participate in?
= digestion and absorption of fats and excretion of products of metabolism (including drug metabolites)
describe the rate of bile production?
= continuously, 0.6-1.2L per day by combined secretion from hepatocytes and bile duct cells (cholangiocytes)
describe the state bile is in between meals and during meals.
Between meals
= stored and concentrated in gall badder (sphincter of Oddi closed)
During meals
= chyme in duodenum stimulates gall bladder smooth muscle to contract (via CCK and vagal impulses)
= sphincter of Oddi opens (via CCK)
= bile spurts into duodenum via cystic and common bile ducts (mixed with bile from liver)
what role does neutral/slightly alkaline bile have?
Assists in;
- micelle formation
- neutralisation of chyme
- pH adjustment for digestive enzyme action
- protection of mucosa
what do hepatocytes secrete?
= primary juice into canaliculi which drains into biliary ductules and ducts
what do secretions from hepatocytes contain?
1) primary bile acids
- mainly colic and chenodeoxycholic acids (fraction of which are dehydroxylated by bacteria in gut to form secondary bile acids, deoxycholic acid and lithhocholic acid)
2) water and electrolytes, e.g. Na+, K+, Ca2+, Cl- and HCO3-
3) lipids and phospholipids (lecithin)
4) cholesterol (excess cholesterol may precipitate into microcystals that aggregate into gall stones = cholelithiasis)
5) IgA
6) bilirubin
7) metabolic wast and conjugated drug metabolites
what is the most common pathology of the biliary tract?
= cholelithiasis
what is cholelithiasis?
= concentration of bile in gall bladder (caused by re-absorption of water) producing a super-saturated solution that is unstable.
- cholesterol may crystallise and over time grow into a gall stone
what is the best treatment fo symptomatic stones, e.g. causing cholangitis or pancreatitis?
= laparoscopic cholecystectomy
what could be used for patients with unimpaired gall bladder function who have small/medium sized radiolucent stones which it dissolves, and diarrhoea could be an adverse effect?
= ursodeoxycholic acid
what 2 analgesias could be used for biliary colic?
1) morphine
- may worsen pain due to constriction of sphincter of oddi and increased intra-biliary pressure
2) buprenorphine and pethidine are alternatives
how can biliary spasms be relived?
1) atropine
2) glyceryltrinitrate (GTN)
how much of bile salts entering the duodenum is lost to the faeces?
a small fraction (5%)
Consequently, what happens to most of bile salts entering the duodenum?
= re-absorbed by activate transport in terminal ileum, undergoing enterohepatic recycling
what happens to a fraction of the primary bile acids (cholic and chenodeoxycholic)?
= dehydroxlated by bacteria in gut to form secondary bile acids (deoxycholic and lithocholic) all of which are returned to the liver.
- secondary bile acids, upon returning to the liver, are conjugated with glycine or taurine, and recycle as bile salts (of Na+ and K+)
what is a term used to describe a group of bile acid sequestrants?
what are 3 examples of bile acid sequestrants?
resins
- colveselam
- colestipol
- colestyramine
describe the absorption of bile acid sequestrants.
Consequently, describe how they act?
- neither digested, nor absorbed, by the gut.
- act by binding to bile acids, preventing their re-absorption
what do bile acid sequestrants lower indirectly?
How do they do this? (3)
= lower plasma LDL-cholesterol indirectly
- promote hepatic conversion of cholesterol to bile acids
- increase cell surface expression of LDL-receptor in hepatocytes
- increase clearance of LDL-cholesterol from plasma
what are 3 clinical uses of bile acid sequestrants?
1) hyperlipidaemia
2) cholestatic jaundice
3) bile acid diarrhoea
what are the 3 limitations and adverse effects of bile acid sequestrants?
1) unpalatable, inconvenient
2) often causes diarrhoea
3) reduced absorption of fat-soluble vitamins, and some drugs (e.g. thiazide diuretics)
how can drugs be described?
= xenobiotics
what 2 things does drug metabolism act to do?
1) convert parent drugs to more polar metabolites that aren’t readily re-absorbed by kidney (from renal tubules), facilitating excretion
2) convert drug metabolites the are usually pharmacologically less active than parent compound
what 3 features do metabolites have?
1) may be converted form inactive pro-drugs to active compounds (e.g. enalapril to enalaprilat) or gain activity (e.g. codeine to morphine(
2) may have unchanged activity (diazepam to nordiazepam)
3) may possess a different type of action (aspirin - anti-inflammatory and anti-platelet) vs salicylic acid (anti-inflammatory NOT anti-platelet)
what is the main organ of drug metabolism?
the liver
- butt GI tract, lungs and plasma also have activity
True or False
Drugs metabolism often (but not invariably) proceeds in one phase.
FALSE.
Occurs in two, sequential phases.
describe the 2 phases involved in drug metabolism.
1) phase 1 - oxidation, reduction and hydrolysis
= makes drugs more polar, adding chemical reactive groups (handle) permitting conjugation (functionalization)
2) Phase 2 - conjugation
= adds an endogenous compound increasing polarity
e.g. with glucuronyl, sulphate, methyl, acetyl, glycol or glutathione groups
Yes or No.
Some drugs are excreted unchanged?
YES.
Describe the two phases of drug metabolism of aspirin.
ASPIRIN (drug) catabolism SALICYCLIC (derivative) anabolism GLUCURONIDE (conjugate)
what do haem proteins located in the endoplasmic reticular of liver hepatocytes mediate?
- oxidation reactions (phase 1) of many lipid soluble drugs
what family do haem proteins comprise to?
cytochrome P450 (CYP) family of monooxyygenase
E.G. CYP3A4 3 = gene family A = gene sub-family 4 = individual gene
what are the 3 main gene families in human liver?
CYP1
CYP2
CYP3
what do phase 2 reactions usually result in?
= inactive products again usually occurring in liver.
what do phase 2 reactions involve?
= conjugation of chemically reactive groups (Hydroxyl, thiol, amino) with glucuruonyl, sulphate, methyl or acetyl groups
what happens in a gluruonidation reaction?
involves transfer of glucuronic acids to electron rise atoms of substrate (N, O, S) forming amide, ester, or thiol bonds
UDP-ALPHA-GLUCURONIDE
glucuronyl transfer using UDP-glucuronyl transferase
GLUCURONIDE
- many endogenous substances are subject to glucuronidation (e.g. adrenal corticosteroids, bilirubin)
what is hepatic encephalopathy (HE)?
= decline in brain function as a result of severe liver disease
what happens in hepatic encephalopathy?
= severe hepatic failure, detoxification of ammonia (NH3), via urea cycle, to urea (excreted by kidneys) fails
- causing blood NH3 levels to rise (hyeprammonemia) exerting a toxic effect upon CNS causing inco-ordination, drowsiness, coma and ultimately death due to cerebral oedema
what are 2 treatment options used to treat hepatic encephalopathy?
1) lactulose
- semi-synthetic disaccharide of fructose and lactose which is;
= not digested or absurd by SI
= when broken down in colon, acidifies the stool (reducing pH)
= converts ammonia to ammonium (NH4+) which is not absorbed
2) antibiotics
e.g. neomycin, rifamixin
= minimally absorbed
- supresses colonic flora and thus inhibits ammonia generation
