Physiology and Pharmacology of the Liver

Question 1

What processes of carbohydrate metabolism is the liver involved in?

Answer 1

Gluconeogenesis, glycolysis, glycogenesis, glycogenolysis.

Question 2

What processes of fat metabolism is the liver involved in?

Answer 2

Processing of chylomicron remnants, synthesis of lipoproteins (for export) and cholesterol (for steroid hormone and bile acid synthesis), ketogenesis (in starvation).

Question 3

What processes of protein metabolism is the liver involved in?

Answer 3

Synthesis of plasma proteins, transamination and deamination of amino acids, conversion of ammonia to urea.

Question 4

What hormones are deactivated by the liver?

Answer 4

Insulin, glucagon, ADH (vasopressin), steroid hormones.

Question 5

What hormones does the liver activate?

Answer 5

Conversion of thyroid hormone (also occurs elsewhere), conversion of vit D to 25-hydroxyvitamin D2 (calcifediol, further activation occurs in the kidney).

Question 6

What does the liver store?

Answer 6

Fat soluble vitamins, water soluble vit B12 (hydroxycobalmin), iron, copper and glycogen.

Question 7

What are the 2 destinations of the proteins produced by the liver?

Answer 7

Metabolic processes of the organ, for export.

Question 8

What proteins are synthesised for export by the liver?

Answer 8

Coagulation factors (II, VII, IX and X), proteins C and S, albumin, complement proteins, apolipoproteins, carrier proteins.

Question 9

What are other names of Kupffer cells?

Answer 9

Liver phagocytes, stellate cells.

Question 10

What are the functions of Kupffer cells?

Answer 10

Digest/destroy particulate matter (e.g. bacteria) and senescent (old) erythrocytes.

Question 11

What does the liver produce to protect the body from attack?

Answer 11

Produce the immune factors host defence proteins (acute phase proteins).

Question 12

What endogenous substances does the liver detoxify?

Answer 12

Many e.g. bilirubin as a metabolite of haemoglobin breakdown.

Question 13

What exogenous substances (xenobiotics) does the liver detoxify?

Answer 13

Drugs, ethanol (alcohol).

Question 14

What happens to bile between meals?

Answer 14

Stored and concentrated in gall bladder (sphincter of Oddi closed).

Question 15

What is the advantages of bile being slightly alkaline?

Answer 15

Assists micelle formation, neutralisation of chyme, pH adjustment for digestive enzyme action, protection of the mucosa.

Question 16

In bile formation, what do the hepatocytes secrete and where into?

Answer 16

Primary juice into canaliculi which drain into biliary ductules and ducts.

Question 17

What does the primary juice contain?

Answer 17

Primary bile acids, water and electrolytes, lipids and phospholipids, cholesterol, IgA, bilirubin, metabolic wastes and conjugated drug metabolites.

Question 18

When may ursodeoxycholic acid be used in cholelithiasis?

Answer 18

In patients with unimpaired gall bladder function who have small/medium sized radiotranslucent stones which it dissolves.

Question 19

What is an adverse effect of ursodeoxycholic acid?

Answer 19

Diarrhoea.

Question 20

Why may morphine worsen biliary colic?

Answer 20

It may constrict sphincter of oddi and increase intrabiliary pressure.

Question 21

What are alternative analgesics used for severe biliary colic?

Answer 21

Buprenorphine and pethidine.

Question 22

What may relieve biliary spasm?

Answer 22

Atropine or GTN.

Question 23

What are the primary bile acids and when are they converted into secondary bile acids?

Answer 23

Mainly cholic and chenodeoxycholic acids, a fraction are dehydroxylated by bacteria in the gut (deoxycholic acid and lithocholic acid).

Question 24

What electrolytes are found in bile acid?

Answer 24

Sodium, potassium calcium, chloride and bicarbonate.

Question 25

What proportion of secondary bile acids are returned to the liver?

Answer 25

All of them.

Question 26

Name 3 bile acid sequestrants (resins).

Answer 26

Colveselam, colestipol, colestyramine.

Question 27

What is the mechanism of action of bile acid resins?

Answer 27

Bind to bile acids, preventing their reabsorption.

Question 28

What are the clinical uses of bile acid binding resins?

Answer 28

Hyperlipidaemia (limited effect), cholestatic jaundice (itch), bile acid diarrhoea.

Question 29

What are the limitations and adverse effects of bile acid resins?

Answer 29

Unpalatable and inconventient (large doses), frequently cause diarrhoea, reduce absorption of fat soluble vitamins and some drugs e.g. thiazide diuretics.

Question 30

How can the liver convert a drug so that it is not readily absorbed by the kidney, facilitating excretion?

Answer 30

By converting them to more polar metabolites.

Question 31

What is the usual effect of liver conversion on a parent drug?

Answer 31

Makes it less pharmacologically active.

Question 32

What is the conversion of enalapril to enalaprilat an example of?

Answer 32

An inactive prodrug being converted into an active compound.

Question 33

What is the conversion of diazepam to nordiazepam an example of?

Answer 33

Conversion where there is no change in activity?

Question 34

What is the conversion of codeine to morphine an example of?

Answer 34

When a drug gains activity after liver metabolism.

Question 35

Give an example where a metabolite of a parent drug in the liver possesses a different type of action.

Answer 35

Aspirin (anti-inflammatory and anti-platelet activity) becomes salicylic acid (anti-inflammatory, not anti-platelet).

Question 36

What other organs metabolise drugs?

Answer 36

The GI tract, lungs and plasma.

Question 37

What do the 2 phases of liver drug metabolism often involve?

Answer 37

Phase I - oxidation, reduction, hydrolysis. | Phase II - conjugation.

Question 38

Describe phase I of liver drug metabolism.

Answer 38

Makes drug more polar, adds a chemically reactive group (handle) permitting conjugation (functionalisation).

Question 39

Describe phase II of liver drug metabolism.

Answer 39

Adds an exogenous compound increasing polarity e.g. glucaronyl, sulphate, methyl, acetyl, glycyl or glutathione groups.

Question 40

Do drugs have to go through both phases of liver metabolism.

Answer 40

No. Some drugs just do phase I, some just do phase II and some drugs are excreted unchanged.

Question 41

Describe the metabolism of aspirin.

Answer 41

Aspirin -> (phase I) -> salicylic acid -> (phase II) -> glucuronide (conjugate).

Question 42

What are the cytochrome P450 (CYP) family of monooxygenases?

Answer 42

Haem proteins located in the ER of hepatocytes mediating oxidation reactions (phase I) of many lipid soluble drugs.

Question 43

How are cytochrome P450 proteins classified?

Answer 43

CYP followed by a defining set of numbers and letters (e.g. CYP3A4).

Question 44

What are the main gene families of CYP in the human liver?

Answer 44

CYP1, CYP2 and CYP3.

Question 45

After phase II reactions, are products usually active or inactive?

Answer 45

Inactive.

Question 46

Describe glucuronidation (common reaction in phase II).

Answer 46

Transfer of glucuronic acid to electron rich atoms of the substrate (N, O or S forming amide, ester or thiol bonds).

Question 47

Where does the glucuronic acid come from in glucuronidation?

Answer 47

UDP-alpha-glucuronide.

Question 48

What is the enzyme involved in glucuronidation?

Answer 48

UDP-glucuronlyl transferase.

Question 49

Give 2 examples of endogenous substances that are subject to glucuronidation.

Answer 49

Bilirubin, adrenal corticosteroids.

Question 50

What causes hepatic encephalopathy?

Answer 50

Increase in blood ammonia levels due to failure of liver to detoxify ammonia via the urea cycle.

Question 51

Describe the stages of hepatic encephalopathy.

Answer 51

Incoordination, drowsiness, coma and ultimately death due to cerebral oedema.

Question 52

What is the mechanism of action of lactulose in hepatic encephalopathy?

Answer 52

When broken down in the colon it acidifies the stool which converts ammonia into ammonium which is not absorbed.

Question 53

What antibiotics may be used in hepatic encephalopathy?

Answer 53

Neomycin, rifamixin (both poorly absorbed).

Question 54

Why do we use antibiotics in hepatic encephalopathy?

Answer 54

They suppress colonic flora and this inhibit ammonia generation.