Physiology/pharmacology of liver Flashcards
what are the metabolic functions of the liver?
regulation of carbohydrate, lipid and amino acid metabolism
describe the processes in carbohydrate metabolism
hormonally regulated
gluconeogenesis (glucose from amino acids)
glycolysis (form pyruvate/lactate/acetyl CoA)
glycogenesis (store glucose as glycogen)
glycogenolysis (release glucose as needed)
what are the processes in fat metabolism?
processing of chylomicron remnants
synthesis of lipoproteins (VLDLs, HDLs) and cholesterol (for steroid hormone/bile synthesis)
Ketogenesis (temp energy source in starvation) - important for neural function
what are the processes in protein metabolism?
synthesis of plasma proteins
transamination and deamination of amino acids
conversion of ammonia to urea (urea cycle - detoxify)
what is the role of the liver in hormone metabolism?
inactivates/degrades many hormones and activates others
what hormones does the liver deactivate?
insulin
glucagon
ADH/vasopressin
steroid hormone
what hormones does the liver activate?
conversion of thyroid hormone (TH) by deiodini.
.
.
.
what substances are stored in the liver?
fat soluble vitamins (A (in Ito cells), D, E, K (in hepatocytes))
Vit B12 (long term - 3-5 years)
Iron, copper
Glycogen
what is involved in the liver’s synthesis of proteins?
for export:
- coagulation factors II, VII, IX and X and proteins C and S
- albumin
- complement proteins
- apolipoproteins
- carrier proteins (secreted into blood and carries other substances eg. thyroid hormone)
what are Kupffer cells?
like resident macrophages
liver phagocytes that digest/destroy particulate matter (eg bacteria) and senescent (old) erythrocytes
How is the liver involved in protection?
Kupffer cells
production of immune factors
- host defence proteins (acute phase proteins)
how is the liver involved in detoxification?
detoxifies many…
.
.
what does bile do?
participates in digestion and absorption of fats and the excretion products of metabolism (including drug metabolites)
how is bile produced?
0.6-1.2L per day by combined secretion from hepatocytes and bile duct cells (cholangiocytes)
where happens to bile between meals?
stored and concentrated (removes bile and water) in the gall bladder (sphincter of oddi closed)
what are the risks of concentrating bile?
components can precipitate out (e.g cholesterol) triggering formation of gall stones
what happens to bile during a meal?
chime in duodenum stimulaes gall bladder smooth muscle to contract and sphincter of oddi to open (via CCK and vagal impulses)
Bile spurts into duodenum via cystic and common bile ducts and mixes with bile from liver
what are the functions of bile?
micelles formation
neutralization of chime
pH adjustment for digestive enzyme action
protection of mucosa
how do hepatocytes secrete primary juice?
secrete juice into canaliculi which drain into biliary ductules and ducts
materials removed from sinusoidal capillary into space of disse, across a membrane?
what blood is in the sinusoidal capillaries?
hepatic portal vein and hepatic artery blood
what is contained in secretion from hepatocytes?
primary bile acids, mainly cholic and chenodeoxycholic acids (a fraction of which are dehydroxylated by bacteria in the gut to form the secondary bile acids, deoxycholic acid and lithocholic acids)
Both the primary and secondary acids are then absorbed and taken back via the hepatic portal vein and can be reused and resecreted into the duodenum
Water and electrolytes (incuding Na, K, Cl, Ca2+ and HCO3)
Lipids and phospholipids
Cholesterol
IgA
Billirubin (renders urine yellow and faeces brown)
Metabolic waste and drug metabolites
what is cholelithiasis?
excess cholesterol relative to bile acids and lecithin may precipitate into microcrystals that aggregate into gall stones
what does dark urine and pale stool indicate?
bilirubin problem
what is the most common pathology of the biliary tract?
cholelithiasis
what is the best treatment for large symptomatic stones?
laproscopic cholecystectomy
when is ursodeoxycholic acid useful?
unimpaired gall bladder function with small/medium sized radiolucent stones (CH stones) which it dissolves
causes diarrhoea
what drugs are used in bilary colic pain?
Not morphine as may constrict sphincter of oddi and increase pressure and worsen pain
- may be used with atropine
Buprenorphine and Pethidine are better alternatives
what does atropine do?
relives bilary spasm
as does GTN
Most bile salts are lost in the faeces, true or false?
false
only 5% lost, most are reabsorbed via active transport in terminal ileum
what are the 2 paths for bile after it has been pumped out of liver?
into gall bladder
into duodenum
what is ASBT?
along with passive transport, brings bile acids (primary and secondary) back into hepatocytes where they can be recycled
what happens to secondary bile acids on returning to the liver?
……..
what are the major bile acid sequestrants (resins)?
colveselam
colestipol
colestyramine
how do resins work?
neither absorbed or digested by gut
bind to bile acids preventing their reabsorption
lower plasma LDL-cholesterol indirectly
- promote hepatic conversion of cholesterol to bile acids
- increase cell curface expression of LDL receptors in hepatocytes
- increase clearance of LDL cholesterol from plasma
what are the clinical uses of resins?
hyperlipidaemia (limited effect)
Cholestatic jaundice (itch)
Bile acid diarrhoea (bile acid overload)
what are the limitations and side effects of resins?
taste bad and require large doses
frequently cause diarrhoea
reduce absorption of fat soluble vitamins
what are the major phases of drug metabolism?
phase 1:
- mediated mainly by cytochrome p450 enzymes
- add polar group to parent drug compound either by oxidation (p450), reduction, hydrolysis
If a drug is lipophilic it is filtered by kidney then reabsorbed as cant be excreted, adding a polar group makes it easier for the kidney to excrete
functionalization = adding chemically active group that can be attacked by phase 2 reaction
Phase 2:
- products of phase 1 are conjugated, usually by glucuronyl, sulphate, methyl, actyl, ………….
what are prodrugs?
need metabolic activation to activate the drug to work (eg. codeine)
explain the 2 phases of metabolism of aspirin
phase 1:
- catabolic conversion of drug to derivative (……)
phase 2:
- anabolic conversion of derivative to……….
what happens when detoxification of ammonia goes wrong?
blood ammonia levels rise causing hepatic encephalopathy which affects CNS
- drowsiness
- incoordination
- coma
- death
how is hepatic encephalopathy treated?
lactulose (acidifies stool reducing pH and converts ammonia to ammonium which is not absorbed)
Antibiotics (neomycin, rifamixin) - suppress colonic flora and inhibit ammonia generation
