Physiology and Pharmacology of the Liver Flashcards
Describe the blood supply to the liver
Dual supply in and single supply out
What are all hepatocytes in contact with?
Blood from both the hepatic portal vein and the hepatic artery
Where does arterial and venous blood mix
In the liver sinusoids
What shape is a cross section of each lobule
Hexagonal
What is found in the centre of each lobule
a branch of the hepatic vein (central vein)
What is found in each of the 6 corners of each lobule
A triad (portal triad)
What is in each portal triad
A branch of the hepatic portal vein
A branch of the hepatic artery and
A bile duct
What is arranged as hepatic plates?
Cords of hepatocytes
Blood flows inwardly through what to the central vein
Sinusoids
Bile secreted by hepatocytes flows outwardly through what to the bile duct
Canaliculi
What are hepatocytes arranged in between
Sinusoids in plates two cells thick
What does the basolateral membrane face
The space of Disse
What is the space of Disse
An extracellular gap between the pericellular space and the endothelial cells that line the fenestrated sinusoids
What forms the canaliculi
The apical membrane of adjacent hepatocytes
Sinusoidla spaces contain which 3 types of cells
Endothelial cells
Kuppfer cells
Stellate (lto) cells
What do endothelial cells allow the movement of?
Solutes but not cells
What type of cells remove particulate matter (bacteria)
Kuppfer cellls
Where do the Stellate cells lie and what is their role?
Within the space of Disse
Important for the storage of vitamin A and may play a role in fibrosis and cirrhosis in liver injury
Describe the sequence of the intraheaptic bile system
Canaliculi Terminal bile ductules Perilobar ducts Interlobar ducts Septal ducts Lobar ducts 2 hepatic ducts The common hepatic duct
How much bile is produced per day
0.6-1.2 litres per day
Where is bile between meals
Stored and concentrated in the gall bladder - the sphincter of Oddi is closed
What happens to bile during a meal
Chyme in the duodenum stimulates gall bladder smooth muscle to contract and bile spurts into the duodenum via the cystic and common bile ducts
What is the role of bile
It participates in the digestion and absorption of fats
During meals, what is the ionic composition of bile similar to
Plasma
Why does the flow rate of bile increase during meals
In response to secretin released from duodenal S cells
What does the slightly alkaline pH of bile contribute to?
Micelle formation
Neutralization of chyme
pH adjustment for digestive enzyme action
Protection of the mucosa
What do hepatocytes secrete and where?
Primary juice in the canaliculi which drain in the the biliary ductules
What is hepatic bile composed of
Primary bile acids mainly cholic and chenodeoxycholic acids Water and electrolytes Lipids and phospholipids Cholesterol IgA Bilirubin
What is bilirubin a product of
The porphyrin component of haemoglobin
Is the total amount of bile salts in the body smaller or larger than the total amount of bile salts emptied into the duodenum during digestive activity
Much smaller
Where are most bile salts reabsorbed and how?
In the terminal ileum and by active transport
What do bile salts undergo?
Enterohepatic recycling
What prevent reabsorption and lower plasma cholesterol?
Resins that bind bile salts eg colestyramine and colestipol
How much bile salt is lost in the faeces
about 5%
How is bile salt synthesised?
From cholesterol in a series of 14 reactions
What first mediates the synthesis of bile salts
Cholesterol 7 alpha hydroxylase
The rate of bile salt synthesis is dependent upon what?
The hepatic portal blood concentration of the salts - low concentration - stimulation and high concentration inhibits synthesis
Secretion across the apical membrane is by what mechanism?
Active transport
What causes gall bladder contraction and relaxation of the sphincter of Oddi
Cholecystokinin
What does secretin cause?
Aqueous alkaline bile secretion
What is the role of vagal activity
This produces a mild secretory response in the cephalic phase of digestion
What is the most common pathology of the biliary tract
Cholelithiasis (formation of gallstones)
What are the options for gall stones
Surgery or the use of ursodeoxycholic acid
What is the most common analgesic used for biliary pain
Morphine
What is the side effect of using morphine n terms of GI
It constricts the sphincter of Oddi
What drugs can be used for the relief of biliary spasm
Atropine or GTN
What alternative analgesics can be used for biliary pain
Buprenorphine
Pethidine
What is the main organ of drug metabolism
Liver
GI tract, lungs and plasma also have an activity
Drug metabolism acts to convert parent drugs to what?
More polar metabolites that are not readily reabsorbed by the kidney
How does drug metabolism often proceed
In 2 sequential phases
What happens in phase 1 of drug metabolism
The liver makes the drug more polar and adds a chemically reactive group to permit the conjugation
What happens in phase 2 of drug metabolism
The liver adds an endogenous compound increasing polarity
What is an example of a drug which undergoes the two phases of drug metabolism
Aspirin
What are the 2 phases of metabolism of aspriin
Catabolic - drug in converted to the derivative
Anabolic - The derivative is converted to the conjugate
What mediates the oxidation reactions of many lipid soluble drugs in the liber
Haem proteins
What are some of hte main gene families in the human liver?
CYP1, CYP2 and CYP3
What does the drug enter the monooxygenase P450 cycle as
As a drug substrate, RH
What is essential for this cycle
Molecular Oxygen to provide 2 Oxygen atoms
What happens to the oxygen atoms
One is added to the drug to yield the hydroxyl product ROH which leaves the cycle
The other combine with protons to form water
What do phase 2 reactions usually result in
Inactive products
Where do phase 2 reactions usually ocur
Liver
What does phase 2 reactions involve
The conjugation of chemically reactive groups
What is a common reaction involving the transfer of glucuronic acid to electron rich atoms of the substrate
Glucuronidation
Name 2 substances which are subject to glucuronidation
Bilirubin and adrenal corticosteroids
