Physiology and Pharmacology of the Liver Flashcards
What is the liver’s blood supply?
75% hepatic portal vein
25% hepatic artery
Describe the passage of blood through the liver
Enters via the hepatic portal vein and the hepatic artery. Goes through venules and arterioles, then mixes in the liver sinusoids (fenestrated capillaries).
It then drains to the central vein of the liver lobule, then into branches of hepatic veins, then drains into a hepatic vein.
What shape is each liver lobule?
Hexagonal in cross section
What is at the centre of each liver lobule?
A branch of hepatic vein at its centre (central vein)
What is at each corner of the lover lobules?
A portal triad:
A branch of hepatic portal vein
A branch of hepatic artery
A bile duct
How are hepatocytes arranged in the lobules?
In cords, arranged as hepatic plates
Which direction does blood flow through the sinusoid?
Inwardly, towards the central vein
What does bile flow through? Which direction does it flow in?
It flows outwardly to the bile duct through canaliculi
How are hepatocytes arranged between the sinusoids?
What do the basolateral membranes of these cells face?
In plates, 2 cells thick.
The basolateral membranes face a pericellular space between these cells and the endothelial cells that line the sinusoids, called the space of Disse.
What does the apical membrane of the hepatocytes between the sinusoids create?
The apical membrane is grooved
Forms the canaliculi for bile
What do sinusoidal spaces contain?
Endothelial cells that form a fenestrated structure
Kuppfer cells: macrophages resident to the sinusoidal vascular space- these removed particulate matter and senescent erythrocytes
Stellate (Ito) cells within the space of Disse: important for storage of Vitamin A, may play a role in fibrosis and cirrhosis
How much bile is produced per day?
It is produced continuously, 0.6-1.2 litres per day
Where is bile between meals?
It is stored and concentrated in the gall bladder
What happens to bile during a meal?
Chyme in the duodenum stimulates gall bladder smooth muscle to contract via CCK and vagal impulses.
The sphincter of oddi opens (via CCK)
Bile spurts into the duodenum via cystic and common bile ducts (mixed with bile from the liver)
What secretions make up bile?
Secretion of hepatocytes
Secretion of cholangiocytes
The secretions mix in the ducts
What does hepatic bile consist of?
Primary bile acids: mainly cholic and chenodeoxycolic acids.
These form bile salts with Na+ and K+. Many are conjugated to glycine or taurine. Some are conjugated to sulphate or glucuonate.
Water and electrolytes including Na, K, Ca, Cl and HCO3 ions.
Lipids and phospholipids e.g. lecithin
Cholesterol
IgA
Bilirubin
What may excess cholesterol relative to bile acids and lecithin precipitate into?
Microcrystals that aggregate into gallstone (cholithiasis)
What can be used to dissolve non-calcified cholesterol gallstones?
Ursodeoxycholic acid
What percentage of the volume of bile does secretion from bile duct cells (cholangiocytes) contribute to?
25%
What does the secretion from cholangiocytes comprise of?
Similar composition to alkaline pancreatic juice
aqueous, alkaline, Na+, K+, Cl-, HCO3-rich
What happens to the flow rate of secretion from cholangiocytes during meals?
During meals flow rate increases in response to secretin released from duodenal S cells
HCO3-/Cl- exchange occurs across the duct cell apical membrane – reduced at high flow rate - therefore HCO3- content increases
What proportion of the bile salts that enter the duodenum is lost in the faeces?
What happens to the rest?
5%
Most is reabsorbed by active transport in the terminal ileum and undergoes enterohepatic recycling
Name 2 resins that bind bile salts to prevent reabsorption of cholesterol and lower plasma cholesterol?
Colestyramine
colestipol
How are bile salts transported from the ileum to the into the enterocytes?
The Na+/bile salt transporter ASBT
What mediates the basolateral transport of bile salts into the portal circulation from the enterocytes?
Organic solute transporter ost-alpha/ost-beta
Which transporter transports bile salts back into the liver from the portal circulation?
mainly NTPC, Na-taurocholate cotransporting polypeptide
What is the starting point for bile salt synthesis?
How many reactions are involved in the pathway?
Which enzyme mediates it first?
Synthesis is from cholesterol in a series of 14 reactions, first mediated by cholesterol 7-alpha-hydroxylase (CYP7alpha1) to form the primary bile salts.
What is the rate of synthesis of bile salts dependent on?
the hepatic portal blood concentration of the salts:
Low concentrate stimulates synthesis
High concentration inhibits synthesis
What does CCK cause to happen?
causes gall bladder contraction and relaxation of the sphincter of Oddi
What does secretin cause to happen?
causes aqueous alkaline bile secretion
What does vagal activity cause?
produces a mild secretory response in the cephalic phase of digestion
What is the most common pathology of the biliary tract?
cholelithiasis
How is cholelithiasis treated?
Surgery is the usual option, but ursodeoxycholic acid may be useful
What analgesics may be used to relieve the pain in biliary colic?
Morphine – but constricts the sphincter of Oddi; buprenorphine and pethidine are alternatives
What may be used for relief of biliary spasm?
Atropine, or glyceryltrinitrate (GTN)
What does drug metabolism in the liver act to do?
Convert parent drugs to more polar metabolites that are not readily reabsorbed in the renal tubules, facilitating excretion
Convert drugs to metabolites that are usually pharmacological less active than the parent compound. Less frequently, metabolites may:
gain activity (e.g. prodrugs)
have unchanged activity
possess a different type of activity
What is the main organ of drug metabolism?
Which other parts of the body have metabolic activity of drugs?
The liver
the G.I. tract, lungs and plasma also have activity
How many phases are involved in drug metabolism?
What do they each do?
Drug metabolism often proceeds in two, sequential, phases.
Phase 1: Makes drug more polar, adds a chemically reactive group (a ‘handle’) permitting conjugation
Reactions involved are oxidation, reduction and hydrolysis
Phase 2: Adds an endogenous compound increasing polarity, e.g. glucuronyl, sulphate, methyl, acetyl, glycyl or glutathione groups
This is conjugation
Do all drugs undergo both phases of drug metabolism?
No- some undergo both phases, some may only undergo Phase 1 orPhase 2 and some are excreted unchanged.
