Week 3 Term 1

functions of the liver

functions of the liver

bile production, metabolism, detoxification of blood

where does the coeliac artery lead to

stomach, spleen and hepatic artery

where does the superior mesenteric artery lead to

intestine and pancreas

where does the inferior mesenteric artery lead to

(lower) intestine

where does the liver receive blood from

hepatic artery and portal vein

how much bile does the liver produce daily

250-1500ml

what are the major secretions of hepatocytes

bile salts, phospholipids (lecithin), bile pigment (bilirubin), cholesterol, inorganic ions

why are hepatic sinusoids leaky

allow more contact between blood and hepatocytes

what is the role of bile salts from hepatocytes

used in lipid digestion and absorption

where do bile salts derive from

cholesterol

circulation of bile salts

• liver synthesises

• bile salts to gall bladder and duodenum

• moves through duodenum to ileum

• bile salt removed from ileum by entering hepatic portal vein or removal in faeces

• bile salts in hepatic portal vein recycled to liver (where some synthesis occurs again)

where do bile pigments come from

breakdown of haemoglobin conjugates with glucuronic acid

use of glucuronic acid in bile pigment formation

increases polarity and solubility in water

how does bile enter the gall bladder

bile flow to duodenum is prevented by closures of sphincter of oddi so will instead enter gall bladder

why do bile salts and pigments become concentrated in the gall bladder

reabsorption of water and salt in gall bladder

what causes sphincter of oddi relaxation

CCK and neural influences (CCK causes sphincter to relax allowing bile into duodenum as well and pushing some bile out of the gallbladder)

when will bile pass to the duodenum instead of the gall bladder

after a meal

when will bile pass to the gall bladder instead of the duodenum

during relaxation

where are lipoproteins formed

liver

where are plasma proteins and clotting factors synthesised

liver

effect of less albumin in blood

more leakage of water to outside of cells (ascites)

liver endogenous molecules that are controlled

insulin, glucagon, aldosterone, female sex hormones

liver exogenous molecules that are controlled

drugs (some converted to active compound)

mechanisms involved in liver metabolism

oxidation, reduction, methylation, conjugation

describe jaundice

bilirubin accumulation in plasma producing yellowing of skin, sclera and mucous membranes. may produce kernicterus which can lead to nerve degeneration in brain

treatment of jaundice

light (breaks down pigment)

describe haemolytic jaundice

excessive haemolysis of RBC (reaches capacity for excretion of RBC)

describe intrahepatic jaundice

defects in conjugation or secretion of bilirubin by hepatic cells (common in acute)

describe obstructive jaundice

blockage of bile ducts

describe physiological jaundice of newborns

babies have poor capacity for conjugating biluribin

what causes acute hepatitis

hepatitis A, B, C (viral) and drugs (eg paracetamol)

what causes chronic hepatitis

hepatitis B, C (viral)

define cirrhosis

necrosis of liver cells replaced by fibroblasts

causes of cirrhosis

alcohol, hepatitis B and C

treatment for cirrhosis

no treatment, just stop causative effect (or organ transplant)

describe layers of GI tract from lumen to outside

mucosa, submucosa, submucosal plexus, inner circular muscle, myenteric plexus, outer longitudinal muscle

name of GI pacemaker cells

interstitial cells of cajal (ICCs)

what rhythm do ICCs pacemaker cells form

basal electrical rhythm (BER)

what does VIP do to smooth muscle cells in GI tract

relax

what does ACh do to smooth muscle cells in GI tract

contract

direction of food movement in GI tract

unidirectional

what nervous control increases GI motility

parasympathetic nerve activation

what nervous control decreases GI motility

sympathetic nerve activation (NA)

how does sympathetic nerve activation decrease GI motility

directly via beta adrenoceptors and indirectly by decreasing ACh release via alpha-2 adrenoceptors

stages of GI motility

mastication (oropharyngeal) and deglutition (oesophageal)n

what is the role of zones of elevated pressure (ZEP) in the GI tract

prevent transit from one region to another (eg backflow)

how is peristalsis initiated

mechanoreceptors in pharynx detect food bolus which initiates peristaltic wave controlled by vagal nerves (gravity assisted)

what controls GI tract smooth muscle excitability

• myogenic properties of smooth muscle cells

• activity of intrinsic nerves

• activity of extrinsic nerves

• hormones or locally produced chemicals

when can BER from the GI pacemaker cells cause a peristaltic wave

when underlying smooth muscle is at it's most excitable and is able to reach the threshold potential

why are peristaltic waves weak for the first hour after eating food

to allow gastric contents to mix and make room for the food bolus

how is relaxation in corpus and fundus induced

by vagal relaxation fibres stimulated by oesophageal and gastric distension which is mediated by VIP

stimulatory GI tract motility hormones

gastrin (antrum) and motility (small intestine)

inhibitory GI tract motility hormones

gastrin (proximal stomach), secretin, CCK, NO

how does the meal composition of food eaten affect GI tract motility

• larger food volume increases rate of gastric emptying

• size of fragments of food

• osmolarity (greater or smaller than 200mOsm slows rate of emptying)

• excess acid slows gastric emptying

• more fat slows gastric emptying

2 types of contraction in small intestine

segmenting and peristaltic

describe segmenting contraction in the small intestine

occurs in circular muscle and move chyme to and fro to increase exposure to mucosal surface

describe peristaltic contraction in the small intestine

occurs in longitudinal muscle over short distances after a meal

describe migrating motility complex (MMC)

occasional propulsive movement propagating over long distances (peristaltic contractions)

what is the role of ileal-caecal sphincter (ZEP) in the large intestine

prevent retrograde movement of bacteria from the colon during movement of chyme

describe the movement of the large intestine during digestion

slow and non-propulsive (Haustral contractions) to knead contents (similar to segmentation in SI)

describe movement of faeces out of the rectum

• arrival of faecal material stimulates sensory nerves

• causes peristaltic wave in colon

• internal anal sphincter relaxes

how is faeces held in by the anus

external sphincter of anus has voluntary control

how does straining increase defecation volume

increases intra-abdominal pressure on colonic and rectal walls

what will a change in absorption effect (AUC, Tmax, F, V, CL, T1/2)

AUC, Tmax, F (only t1/2 if absorption greatly prolonged)

what will a change in distribution effect (AUC, Tmax, F, V, CL, T1/2)

V, T1/2

what will a change in elimination effect (AUC, Tmax, F, V, CL, T1/2)

AUC, CL, T1/2

what effects rate of passive diffusion

• concentration gradient across membrane

• surface area

• membrane thickness

• lipid solubility

• molecule size

why do charged drugs need to become uncharged

only uncharged drugs can cross cell membrane

how do you find the pKa (ionisation constant) of a drug

pH at which drug is 50% charged and 50% uncharged

are weak base drugs more charged or more uncharged in a decreased pH (more acidic)

more charged

are weak acid drugs more or more uncharged in a decreased pH (more acidic)

more uncharged

are weak acid or weak base drugs better for absorption in stomach and intestine and entry into the brain

weak base drugs

do weak acid or weak base drugs have better absorption in the stomach

weak acids

why are weak acid drugs easily absorbed by the stomach

A- + H+ = HA (HA can be absorbed as its uncharged)

why do some drugs need to be taken with food

takes longer for drug to be absorbed

describe acid stable drugs

slower absorption in stomach

describe acid labile drugs

stays in stomach for longer and is more easily broken down

are acid stable or acid labile drugs taken with food normally

acid labile

define human microbiome

all microorganisms that live on or in the body forming a dynamic and interactive microecosystem crucial for maintaining health

main locations on body of human microbiomes

skin, mouth, lungs, GI tract, eye, hair follicles, nasopharyngeal, genital tract (male and female)

normal processes that can be affected by the human microbiome

body weight, mood, cholesterol level, sleep, vitamin absorption, cancer, blood pressure, response to drugs,

factors influencing microbiome diversity

living environment, drugs, birth mode, diet, immune disease, metabolic disease, colorectal cancer, autism, age

factors leading to opportunistic infection

compromised immunity, antibiotic suppression of normal flora, breach of physical barriers, impaired normal clearance mechanisms (smoking impairing cilia)

how can lipid soluble drugs be excreted

metabolised by liver, gut or blood to become a water soluble metabolite which can be excreted by the liver or kidney

how are volatile drugs (eg anaesthetics) excreted

via lungs

examples of drugs inactivated by metabolism

warfarin, phenytoin

examples of drugs activated by metabolism (prodrugs)

clopidogrel, codeine

timeline of paracetamol overdose

• paracetamol metabolised

• 10% metabolism by CYP

• metabolism by these creates NAPQI which is a toxic metabolite

• metabolite has toxic reactions with proteins and nucleic acids which can lead to liver failure

antidote for paracetamol overdose

N-acetylcysteine

what occurs during phase 1 of drug metabolism

introduction/unmasking of functional group which somewhat increases water solubility using cytochrome P450

what occurs during phase 2 of drug metabolism

conjugation with endogenous chemical at functional centre which gives a great increase in water solubility

Non-viral causes of hepatitis

leptospirosis, brucellosis

preicteric clinical features of acute viral hepatitis

malaise, anorexia, nausea, abdominal discomfort, pyrexia (fever)

interim clinical features of acute viral hepatitis

pale stool, dark urine, jaundice

describe the hepatitis A virus

• RNA genome

• positive single strand

• entry via contaminated food or water

• excreted in faeces

consequences of hepatitis A

• asymptomatic infection (worse as adult)

• acute icteric hepatitis

• fulminant hepatitis (rare)

prevention of hepatitis A

care with food and water, vaccination (whole killed virus)

describe the DNA of hepatitis B viruses

partially double stranded (one circular DNA and a partial second strand) (hepadnavirus)

envelope of hepatitis A vs B

hepatitis A has no envelope

outcomes of acute hepatitis B infection

• subclinical infection

• acute icteric hepatitis

• fulminant hepatitis

• chronic infection (10%)