Physiology + Disease of the Liver, Drug Metabolism Flashcards
Describe the blood supply to the liver
70% venous blood from the hepatic portal vein
30% arterial flow from the hepatic artery
Where does the portal vein carry venous blood from?
Stomach
Small intestine
Large intestine
Pancreas
Spleen
What is the main cell type in the liver called?
Hepatocyte
How are hepatocytes arranged?
Hepatocytes are arranged in lobules around a central vein.
Reticuloendothelial cells surround hepatocytes
Describe the functional zonation of liver lobules
Zone I - periportal (far from central vein) hepatocytes. Oxidative metabolism, gluconeogenesis, urea synthesis. Most oxygenated.
Zone II
Zone III - pericentral (near vein) hepatocytes. Drug metabolism, glycolysis, lipogenesis. Least oxygenated
Where in the lobule does gluconeogenesis take place?
Zone I - most oxygenated, furthest area away from central vein
Where in the lobule does drug metabolism, glycolysis and lipogenesis take place?
Zone III - closest to the central vein of the lobule
Describe the venous supply within a liver lobule
Sinusoids (vascular spaces) separate plated of hepatocytes.
Blood from sinusoids converges on a central vein of a lobule
Central veins converge on the hepatic vein
List the major cell types of the liver
Hepatocytes
Cholangiocytes
Sinusodial epithelial cells (line the sinusoids)
Reticuloendothelial cell meshwork contains:
Endothelial cells
Kupffer cells - anchored to wall of sinusoids
Lipocytes
What is the space of Disse?
What is found in this space?
The space between a sinusoid and a plate of hepatocytes
Lipocytes are found here - they store fat and secrete collagen in disease states
Which cell types of the liver secretes HCO3- and water?
Where are they found?
Cholangiocytes
Line the bile ducts of the liver
What do cholangiocytes produce?
HCO3-
Water
Name 8 functions of the liver:
Energy metabolism and substrate interconversion
Synthesis of plasma proteins
Drug metabolism and detoxification
Immune functions
Production of bile
Cholesterol processing
Storage of vitamins and minerals
Excretion of bilirubin
How is the liver involved in carbohydrate metabolism?
Glycogenolysis
Gluconeogenesis
Glycogen synthesis
How is the liver involved in lipid metabolism?
Ketogenesis
Trigylceride synthesis from fatty acids
What coagulation factor is made in the liver?
Fibrinogen
What substance, that is responsible for the breakdown of fibrin, is made in the liver?
Plasminogen
Which 2 binding proteins are made in the liver?
Thyroid-binding globulin (TBG)
Sex hormone binding globulin (SHBG)
Which major plasma protein is made in the liver?
Albumin
Outline the immune function of the liver
Kupffer Cells responsible for immunity in the liver
Macrophages attached to the endothelial cell lining of the sinusoids
Ingest bacteria (by phagocytosis) and inflammatory mediators
What does the gallbladder do to bile?
Stores and concentrates it
Where does bile produced in the liver drain to?
Main bile duct from the liver to the duodenum
In response to food in the duodenum, what are the actions of secretin?
HCO3- secretion from exocrine pancreas
Bile production from liver
In response to food in the duodenum, what are the actions of CCK?
Gallbladder contraction
Enzyme secretion from the exocrine pancreas
What hormone stimulates bile production in the liver, and HCO3- secretion from the pancreas?
Secretin
Which hormone stimulates gallbladder contraction and enzyme secretion from the pancreas?
CCK
What are the 2 components of the exocrine pancreas secretions?
Enzymes
HCO3-
List the 6 major components of bile
Bile salts
(bile acids + taurine)
Lecithin (a phospholipid)
HCO3- and other salts Neutralizes acid in duodenum
Cholesterol
Bile pigments and small amounts of other metabolic end-products.
Trace metals
What is the function of bile salts?
To hold fats in suspension for pancreatic lipase to work
What is the role of HCO3- being excreted in bile?
Neutralises the acidic chyme coming from the stomach
What is the role of hepatocytes in bile production?
Either make the bile products or extract them from the blood
Which component of bile is made by cholangeocytes?
HCO3- (and other salts)
What 4 things to hepatocytes secrete?
Bile salts
Cholesterol
Lecithin
Bile pigments
What 2 things do cholangiocytes secrete?
HCO3-
Water
Once the components of bile have been made, where do they drain to?
Across the canalicular membrane of the hepatocytes and cholangiocytes to the bile canaliculus and then into the bile duct
How are bile salts moved in and out of a bile canaliculus?
Membrane transporters
Different types of transporters to move them in and move them out of the canaliculus
What are the primary bile acids synthesised from?
What are they conjugated to?
Why are they conjugated?
Cholesterol
Primary bile salts are conjugated to taurine
Conjugated to make them more soluble
What does taurine conjugate to?
Primary bile salts
What does glycine conjugate to?
Secondary bile acids
Once a bile acid has been conjugated, what does it then become?
A bile salt
Where do conjugated bile salts move to?
Bile canaliculus
What happens to 95% of the bile salts in the small intestine?
What proportion of these are intact bile salts
They are recycled via the enterohepatic circulation and returned to the liver for use
Of this, 75% are intact bile salts
25% are deconjugated by bacteria to produce primary or secondary bile acids
Where in the small intestine are bile salts reabsorbed?
Terminal ileum
What happens to excess cholesterol?
Moved straight out of the hepatocytes through the bile canaliculus into the faeces
List the 4 functions of bile salts
Emulsification of dietary lipids, rendering them accessible to pancreatic lipases.
Elimination of cholesterol.
Prevention of cholesterol precipitation in the gall bladder.
Facilitation of the absorption of fat-soluble vitamins.
How is cholesterol transported in plasma?
In complexes with lipoproteins (synthesised in the liver)
List 4 functions of cholesterol
Plasma membranes
Component of bile salts
Precursor for steroid hormones
Myelin (neuron axonal ‘wrapping’)
What is the role of the liver in cholesterol processing (6)?
Synthesizes cholesterol from Acetyl CoA.
Synthesizes lipoproteins, which transport cholesterol in plasma.
Exports cholesterol via circulation to body cells for synthesis of key products e.g. steroid hormones.
Exports cholesterol to liver for synthesis of bile salts.
Extracts excess cholesterol from plasma.
Exports excess cholesterol via liver into bile for excretion in faeces.
What vitamins and minerals does the liver store?
Fat soluble vitamins D E A K
Minerals - iron and copper
What is the main bile pigment?
Bilirubin
How is bilirubin formed?
From the breakdown of haem in the spleen and bone marrow
Where is bilirubin exported into?
Bile
What is conjugated with bilirubin?
Which cell in the liver does this?
What is the purpose of this?
Hepatocytes conjugate bilirubin with glucuronic acid to form a polar, water-soluble molecule, which is exported into bile.
When bilirubin is moving through the blood, what is it bound to?
Albumin
Once bilirubin has been conjugated and released into the small intestine, what is it broken down into?
How does this get excreted?
Urobilinogen
Picked up by the portal vein, then excreted in urine
Which blood tests show hepatocyte/hepatitic damage?
ALT (alanin transaminase)
AST (aspartate transaminase)
Which blood tests show bile duct/obstructive damage?
Alkaline phosphotase
Gamma GT
Name the 5 true tests of liver function
Prothrombin time
Bilirubin
Albumin
Urea/creatinine
pH
What causes jaundice?
Failure of the body to excrete bile
Clinically apparent when serum bilirubin is twice above normal concentration - 34uM/L
In which 3 places can gallstones cause an obstruction?
Gallbladder
Bile duct
Major duodenal papillae
What are the 3 layers of the wall of the gallbladder?
Epithelium
Lamina propria
Fibromuscular layer
Which layer of the gallbladder is responsible for contraction?
Fibromuscular layer
List some facts about gallstones
Most are cholesterol based
Associated with high fat diets / hypercholesterolaemia
Can be formed by reduced bile secretion or defective reabsorption of bile salts
List some pros and cons to US investigation
Pros - simple, non-invasive, widely available
Cons - operator dependent, poor specificity, poor views of pancreas
What type of imaging can be used to visualise the biliary system?
ERCP
Endoscopic retrograde cholangio-pancreatography
List the causes of pancreatitis
Idiopathic
Gall stones
Ethanol
Trauma
Steroids Mumps Autoimmune Scorpion bites Hypercalaemia/hypertriglyceridaemia ERCP Drugs
What does the endocrine pancreas secrete?
Insulin
Glucagon
Somatostatin
What does the exocrine pancreas release?
Enzymes
Amylase, trypsin
Chymotripsin, lipase
HCO3-
List some symptoms of chronic pancreatitis
Pain - epigastric region
Pancreatic failure
Diabetes (endocrine)
Malabsorption (exocrine)
What blood results would be raised in biliary obstruction?
Bilirubin
Alkaline phosphatase - raised
GGT - raised
When taking a history from a pancreas patient, what questions would you need to ask?
Alcohol
HTN
Viruses
Farm
Foreign travel
Sexual history
Drugs
What are the 2 types of pancreatic cancer?
Adenocarcinoma
Neuroendocrine
What is a cancer of the bile duct called?
Cholangiocarcinoma
List some pros and cons to using CT to image the pancreas
Pros - widely available, good views of pancreas, transferable images
Cons - radiation exposure, high demand
List some pros and cons to using MRCP to view the pancreas
Pros - good mapping of ducts
Cons - limited availability
List some pros and cons to using MRCP to view the pancreas
Pros - good mapping of ducts
Cons - limited availability
List some pros and cons to using ERCP to view the pancreas
Pros - high sensitivity and specificity
Cons - invasive, technically challenging, complications
What are the 4 phases of pharmacokinetics?
Absorption
Distribution
Metabolism
Excretion
What 3 effects does drug metabolism have on drug activity?
Conversion of drugs to inactive commons:
-most common
Inactive pro-drugs to active drugs:
- prevent adverse effects
- improved distribution
Active metabolites:
-codeine converted to morphine
Where do orally administered drugs go after absorption?
Portal system to the liver
What is ‘first pass metabolism’?
Orally-administered drugs, absorbed by the GI tract, are transported via the portal system through the liver where they are metabolised to an extent before entering the systemic circulation.
Which organ is the major site of drug metabolism?
The liver
In which 2 places are drugs excreted?
Bile
Urine
What is a phase I drug reaction?
Conversion of a drug to an intermediate metabolite by adding a functional group through:
- oxidation
- reduction
- hydrolysis
What is the purpose of phase I drug reactions?
Increase polarity of the drug
Provide a site for phase II (conjugation) reactions
Do phase I reactions make a drug more or less pharmacologically active?
Less active
In what circumstance would a drug not need to undergo phase I metabolism?
If it already has a functional group in its chemical structure
What is the purpose of phase II reactions?
To conjugate a drug to a metabolite to make it more soluble and more easily excreted from the body
Do phase II reactions make a drug more or less pharmacologically active?
Less active
What is the purpose of phase III reactions?
To move conjugated metabolites out of the hepatocytes of the liver where they can be excreted
Once a drug has undergone a phase III reaction, where will it go?
Larger molecules will be excreted in the bile
Smaller molecules will reach the systemic circulation and be excreted via the kidneys
What is the most common type of phase I metabolism reaction?
Oxidation of a drug
Which enzymes catalyses phase I reactions?
Cytochrome P450 enzymes
Discuss cytochrome P450 enzymes
What 3 things need to be present for them to function?
Haem proteins (haem molecule at active site)
Molecular oxygen
NADPH
NADPH cytochrome P450 reductase
What is the mixed function oxidase system?
Molecular oxygen
NADPH
NADPH cytochrome P450 reductase
What is needed for cytochrome P450 enzymes to function
Describe oxidation of a drug by cytochrome P450 enzymes
Involves oxidation and reduction
Catalyses the transfer of one O2 atom to the drug while the other O2 atom is reduced to water
What is the most common cytochrome P450 isoform?
CYP3A
List some phase I reactions that are NOT oxidation by P450
Reductions
Oxidation without P450
- alcohol dehydrogenase
- monoamine oxidase (NA, 5-HT)
Hydrolytic reactions that occur in the plasma and many tissues
-aspirin
What type of chemical reaction are cytochrome P450 enzymes responsible for?
Oxidation reactions
Describe the role of monamine oxidase in phase I reactions
Oxidation of a metabolite without the cytochrome P450 enzymes
Inactivates biologically active amines
- NA
- 5-HT
A patient lacks cytochrome P450 enzymes.
What phase I reactions will be able to take place?
Reductions
Ethanol metabolisiation by alcohol dehydrogenase
Inactivation of NA and 5-HT by monamine oxidase
Hydrolytic reactions
Which enzyme metabolises ethanol?
Alcohol dehydrogenase
Where in the liver are P450 enzymes found?
What else are found here?
On the smooth endoplasmic reticulum of hepatocytes
Conjugating enzymes involved in phase II reactions
What is bilirubin conjugated with in the liver?
Glucuronic acid
Which enzyme conjugates glucronide?
UDP-glucuronyl transferase
What moves hydrophillic metabolites from hepatocytes?
Multi-purpose membrane-bound transport carrier systems
Give an example of a drug administered as a pro-drug and activated by phase I metabolism
ACE inhibitors
Which drug, after phase I metabolism, yields a toxic metabolite?
Paracetamol
What determines the duration of action of digoxin and atenolol?
Renal elimination
These drugs are not inactivated by metabolism - need renal clearance to ‘deactivate’ them (this is the only thing that stops the drug from working
What considerations need to be made when prescribing drugs to neonates?
Hepatic drug-metabolizing enzyme systems are immature.
Renal clearance inefficient
Lower doses of all drugs are needed
Why can metabolic clearance be quicker in children?
CYPs are mature
Relative liver mass and hepatic blood flow are higher
What considerations need to be made when prescribing drugs to children?
Dosages of medicines should be obtained from a paediatric dosage handbook.
Prescribed dosages are judged by considering both age and body surface area.
What considerations need to be made when prescribing drugs to elderly patients?
Capacity for phase I reactions is reduced (liver mass and hepatic blood flow is reduced)
Polypharmacy affects drug metabolism
Rational prescribing - minimise number of drugs used
Start treatment with smallest effective dose
During which phase of drug metabolism are drug interactions likely to occur?
Phase I reactions
Likely to interact with enzymes e.g. cytochrome P450 enzymes
What classes of drugs are CYP3A enzymes responsible for metabolising?
Most calcium channel blockers
Most benzodiazepines
Most HIV protease inhibitors
Most HMG-CoA-reductase inhibitors
Cyclosporine
Most non-sedating antihistamines
Oral contraceptives
Give some examples of CYP3A inhibitors
Fluconazole (antifungal)
Erythromycin (macrolide Abx)
Cimetidine (histamine H2 receptor antagonist)
Grapefruit juice
What effect can CYP3A inhibitors have on drug metabolism?
Reduced drug clearance
Higher plasma concentrations of drug
Potentially toxic drug levels and adverse effects
Give some examples of CYP3A inducers
Carbamazepine
Rifampicin
Rifabutin
Ritonavir
St. John’s Wort - herbal remedy for depression
What effect can CYP3A inducers have on drug metabolism?
Increased clearance of drug
Lower plasma levels of drug
Lack of therapeutic effect
Which drugs can St. John’ Wort commonly interact with?
Warfarin
Anti-epileptics
Oral contraceptives
If someone has low CYP450 activity, what effect will this have on drug metabolism?
Less drug inactivation if CYP responsible - more active drug available at toxic levels
Less drug activation if CYP responsible - pro-drug may become toxic (e.g. paracetamol)
drug may not activate
If someone has high CYP450 activity, what effect will this have on drug metabolism?
More drug inactivation - may require increased dose of drug
More drug activation
- rapid onset
- may require reduced dose to prevent accumulation of drug
Give an example of a drug that is activated by cytochrome P450 enzymes
Codeine
CYP2D6 isoform
List 5 side effects of codeine
N+V
Light-headedness
Dizziness
Sweating
Constipation
List 6 signs of opioid toxicity
Respiratory depression
Skeletal muscle flaccidity
Cold and clammy skin
Bradycardia
Hypotension
Constipation
What effects will liver cirrhosis have of drug metabolism?
Porto-systemic shunting directs drug away from the liver
Increased bioavailabilty of drug because of reduced first-pass metabolism (above)
Hepatocytes are sick or reduced in number
Decreased protein binding
Overall increased bioavailability of drugs in liver disease
Define bioavailability
The proportion of administered drug which reaches the systemic circulation unchanged and is thus available for distribution to the site of action
Define first pass metabolism
The extent of metabolism occurring BEFORE the drug enters the systemic circulation
Which 3 drugs increase in bioavailability in cirrhosis?
Calcium channel antagonist - nicardipine
B-adrenoceptor antagonist - propranolol
Calcium channel antagonists - verapamil
What will happen to the bioavailability of ramipril in liver cirrhosis?
Bioavailability will be reduced - needs first-pass metabolism to activate it
What effect will hypoproteinaemia have on drug bioavailability?
Leads to reduced drug-binding capacity
More unbound pharmacologically active drug to circulate
What 3 things need to be considered when prescribing in liver disease?
Prescribe with care
Drugs metabolised by the liver should be given in smaller doses
Patients with liver disease are more likely to be susceptible to hepatotoxic drugs
If a patient is jaundiced with normal stools and urine, what does this suggest?
Pre-hepatic cause of jaundice (high bilirubin)
If a patient is jaundiced with dark urine and normal stools, what does this suggest?
Hepatic cause of jaundice
Bilirubin has been able to be conjugated and excreted in the urine, causes the darker colour
If a patient is jaundiced with dark urine and pale stools, what does this suggest?
Post-hepatic (obstructive) cause of jaundice
If bile and pancreatic lipase’s are unable to reach the bowel because of a blockage (e.g. in obstructive post-hepatic pathology), fat is not able to be absorbed, resulting in stools appearing pale, bulky and more difficult to flush.
What does prothrombin time assess?
The extrinsic pathway of the clotting cascade
