Physiology and Pharmacology of the Liver Flashcards
What processes of carbohydrate metabolism is the liver involved in?
Gluconeogenesis, glycolysis, glycogenesis, glycogenolysis.
What processes of fat metabolism is the liver involved in?
Processing of chylomicron remnants, synthesis of lipoproteins (for export) and cholesterol (for steroid hormone and bile acid synthesis), ketogenesis (in starvation).
What processes of protein metabolism is the liver involved in?
Synthesis of plasma proteins, transamination and deamination of amino acids, conversion of ammonia to urea.
What hormones are deactivated by the liver?
Insulin, glucagon, ADH (vasopressin), steroid hormones.
What hormones does the liver activate?
Conversion of thyroid hormone (also occurs elsewhere), conversion of vit D to 25-hydroxyvitamin D2 (calcifediol, further activation occurs in the kidney).
What does the liver store?
Fat soluble vitamins, water soluble vit B12 (hydroxycobalmin), iron, copper and glycogen.
What are the 2 destinations of the proteins produced by the liver?
Metabolic processes of the organ, for export.
What proteins are synthesised for export by the liver?
Coagulation factors (II, VII, IX and X), proteins C and S, albumin, complement proteins, apolipoproteins, carrier proteins.
What are other names of Kupffer cells?
Liver phagocytes, stellate cells.
What are the functions of Kupffer cells?
Digest/destroy particulate matter (e.g. bacteria) and senescent (old) erythrocytes.
What does the liver produce to protect the body from attack?
Produce the immune factors host defence proteins (acute phase proteins).
What endogenous substances does the liver detoxify?
Many e.g. bilirubin as a metabolite of haemoglobin breakdown.
What exogenous substances (xenobiotics) does the liver detoxify?
Drugs, ethanol (alcohol).
What happens to bile between meals?
Stored and concentrated in gall bladder (sphincter of Oddi closed).
What is the advantages of bile being slightly alkaline?
Assists micelle formation, neutralisation of chyme, pH adjustment for digestive enzyme action, protection of the mucosa.
In bile formation, what do the hepatocytes secrete and where into?
Primary juice into canaliculi which drain into biliary ductules and ducts.
What does the primary juice contain?
Primary bile acids, water and electrolytes, lipids and phospholipids, cholesterol, IgA, bilirubin, metabolic wastes and conjugated drug metabolites.
When may ursodeoxycholic acid be used in cholelithiasis?
In patients with unimpaired gall bladder function who have small/medium sized radiotranslucent stones which it dissolves.
What is an adverse effect of ursodeoxycholic acid?
Diarrhoea.
Why may morphine worsen biliary colic?
It may constrict sphincter of oddi and increase intrabiliary pressure.
What are alternative analgesics used for severe biliary colic?
Buprenorphine and pethidine.
What may relieve biliary spasm?
Atropine or GTN.
What are the primary bile acids and when are they converted into secondary bile acids?
Mainly cholic and chenodeoxycholic acids, a fraction are dehydroxylated by bacteria in the gut (deoxycholic acid and lithocholic acid).
What electrolytes are found in bile acid?
Sodium, potassium calcium, chloride and bicarbonate.
What proportion of secondary bile acids are returned to the liver?
All of them.
Name 3 bile acid sequestrants (resins).
Colveselam, colestipol, colestyramine.
What is the mechanism of action of bile acid resins?
Bind to bile acids, preventing their reabsorption.
What are the clinical uses of bile acid binding resins?
Hyperlipidaemia (limited effect), cholestatic jaundice (itch), bile acid diarrhoea.
What are the limitations and adverse effects of bile acid resins?
Unpalatable and inconventient (large doses), frequently cause diarrhoea, reduce absorption of fat soluble vitamins and some drugs e.g. thiazide diuretics.
How can the liver convert a drug so that it is not readily absorbed by the kidney, facilitating excretion?
By converting them to more polar metabolites.
What is the usual effect of liver conversion on a parent drug?
Makes it less pharmacologically active.
What is the conversion of enalapril to enalaprilat an example of?
An inactive prodrug being converted into an active compound.
What is the conversion of diazepam to nordiazepam an example of?
Conversion where there is no change in activity?
What is the conversion of codeine to morphine an example of?
When a drug gains activity after liver metabolism.
Give an example where a metabolite of a parent drug in the liver possesses a different type of action.
Aspirin (anti-inflammatory and anti-platelet activity) becomes salicylic acid (anti-inflammatory, not anti-platelet).
What other organs metabolise drugs?
The GI tract, lungs and plasma.
What do the 2 phases of liver drug metabolism often involve?
Phase I - oxidation, reduction, hydrolysis.
Phase II - conjugation.
Describe phase I of liver drug metabolism.
Makes drug more polar, adds a chemically reactive group (handle) permitting conjugation (functionalisation).
Describe phase II of liver drug metabolism.
Adds an exogenous compound increasing polarity e.g. glucaronyl, sulphate, methyl, acetyl, glycyl or glutathione groups.
Do drugs have to go through both phases of liver metabolism.
No. Some drugs just do phase I, some just do phase II and some drugs are excreted unchanged.
Describe the metabolism of aspirin.
Aspirin -> (phase I) -> salicylic acid -> (phase II) -> glucuronide (conjugate).
What are the cytochrome P450 (CYP) family of monooxygenases?
Haem proteins located in the ER of hepatocytes mediating oxidation reactions (phase I) of many lipid soluble drugs.
How are cytochrome P450 proteins classified?
CYP followed by a defining set of numbers and letters (e.g. CYP3A4).
What are the main gene families of CYP in the human liver?
CYP1, CYP2 and CYP3.
After phase II reactions, are products usually active or inactive?
Inactive.
Describe glucuronidation (common reaction in phase II).
Transfer of glucuronic acid to electron rich atoms of the substrate (N, O or S forming amide, ester or thiol bonds).
Where does the glucuronic acid come from in glucuronidation?
UDP-alpha-glucuronide.
What is the enzyme involved in glucuronidation?
UDP-glucuronlyl transferase.
Give 2 examples of endogenous substances that are subject to glucuronidation.
Bilirubin, adrenal corticosteroids.
What causes hepatic encephalopathy?
Increase in blood ammonia levels due to failure of liver to detoxify ammonia via the urea cycle.
Describe the stages of hepatic encephalopathy.
Incoordination, drowsiness, coma and ultimately death due to cerebral oedema.
What is the mechanism of action of lactulose in hepatic encephalopathy?
When broken down in the colon it acidifies the stool which converts ammonia into ammonium which is not absorbed.
What antibiotics may be used in hepatic encephalopathy?
Neomycin, rifamixin (both poorly absorbed).
Why do we use antibiotics in hepatic encephalopathy?
They suppress colonic flora and this inhibit ammonia generation.
