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Block 1 > Physiology + Disease of the Liver, Drug Metabolism > Flashcards

Physiology + Disease of the Liver, Drug Metabolism Flashcards

1
Q

Describe the blood supply to the liver

A

70% venous blood from the hepatic portal vein

30% arterial flow from the hepatic artery

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2
Q

Where does the portal vein carry venous blood from?

A

Stomach

Small intestine

Large intestine

Pancreas

Spleen

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3
Q

What is the main cell type in the liver called?

A

Hepatocyte

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4
Q

How are hepatocytes arranged?

A

Hepatocytes are arranged in lobules around a central vein.

Reticuloendothelial cells surround hepatocytes

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5
Q

Describe the functional zonation of liver lobules

A

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

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6
Q

Where in the lobule does gluconeogenesis take place?

A

Zone I - most oxygenated, furthest area away from central vein

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7
Q

Where in the lobule does drug metabolism, glycolysis and lipogenesis take place?

A

Zone III - closest to the central vein of the lobule

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8
Q

Describe the venous supply within a liver lobule

A

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

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9
Q

List the major cell types of the liver

A

Hepatocytes

Cholangiocytes

Sinusodial epithelial cells (line the sinusoids)

Reticuloendothelial cell meshwork contains:

Endothelial cells

Kupffer cells - anchored to wall of sinusoids

Lipocytes

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10
Q

What is the space of Disse?

What is found in this space?

A

The space between a sinusoid and a plate of hepatocytes

Lipocytes are found here - they store fat and secrete collagen in disease states

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11
Q

Which cell types of the liver secretes HCO3- and water?

Where are they found?

A

Cholangiocytes

Line the bile ducts of the liver

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12
Q

What do cholangiocytes produce?

A

HCO3-

Water

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13
Q

Name 8 functions of the liver:

A

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

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14
Q

How is the liver involved in carbohydrate metabolism?

A

Glycogenolysis

Gluconeogenesis

Glycogen synthesis

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15
Q

How is the liver involved in lipid metabolism?

A

Ketogenesis

Trigylceride synthesis from fatty acids

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16
Q

What coagulation factor is made in the liver?

A

Fibrinogen

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17
Q

What substance, that is responsible for the breakdown of fibrin, is made in the liver?

A

Plasminogen

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18
Q

Which 2 binding proteins are made in the liver?

A

Thyroid-binding globulin (TBG)

Sex hormone binding globulin (SHBG)

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19
Q

Which major plasma protein is made in the liver?

A

Albumin

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20
Q

Outline the immune function of the liver

A

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

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21
Q

What does the gallbladder do to bile?

A

Stores and concentrates it

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22
Q

Where does bile produced in the liver drain to?

A

Main bile duct from the liver to the duodenum

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23
Q

In response to food in the duodenum, what are the actions of secretin?

A

HCO3- secretion from exocrine pancreas

Bile production from liver

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24
Q

In response to food in the duodenum, what are the actions of CCK?

A

Gallbladder contraction

Enzyme secretion from the exocrine pancreas

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25
Q

What hormone stimulates bile production in the liver, and HCO3- secretion from the pancreas?

A

Secretin

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26
Q

Which hormone stimulates gallbladder contraction and enzyme secretion from the pancreas?

A

CCK

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27
Q

What are the 2 components of the exocrine pancreas secretions?

A

Enzymes

HCO3-

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28
Q

List the 6 major components of bile

A

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

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29
Q

What is the function of bile salts?

A

To hold fats in suspension for pancreatic lipase to work

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30
Q

What is the role of HCO3- being excreted in bile?

A

Neutralises the acidic chyme coming from the stomach

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31
Q

What is the role of hepatocytes in bile production?

A

Either make the bile products or extract them from the blood

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32
Q

Which component of bile is made by cholangeocytes?

A

HCO3- (and other salts)

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33
Q

What 4 things to hepatocytes secrete?

A

Bile salts

Cholesterol

Lecithin

Bile pigments

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34
Q

What 2 things do cholangiocytes secrete?

A

HCO3-

Water

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35
Q

Once the components of bile have been made, where do they drain to?

A

Across the canalicular membrane of the hepatocytes and cholangiocytes to the bile canaliculus and then into the bile duct

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36
Q

How are bile salts moved in and out of a bile canaliculus?

A

Membrane transporters

Different types of transporters to move them in and move them out of the canaliculus

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37
Q

What are the primary bile acids synthesised from?

What are they conjugated to?

Why are they conjugated?

A

Cholesterol

Primary bile salts are conjugated to taurine

Conjugated to make them more soluble

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38
Q

What does taurine conjugate to?

A

Primary bile salts

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39
Q

What does glycine conjugate to?

A

Secondary bile acids

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40
Q

Once a bile acid has been conjugated, what does it then become?

A

A bile salt

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41
Q

Where do conjugated bile salts move to?

A

Bile canaliculus

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42
Q

What happens to 95% of the bile salts in the small intestine?

What proportion of these are intact bile salts

A

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

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43
Q

Where in the small intestine are bile salts reabsorbed?

A

Terminal ileum

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44
Q

What happens to excess cholesterol?

A

Moved straight out of the hepatocytes through the bile canaliculus into the faeces

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45
Q

List the 4 functions of bile salts

A

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.

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46
Q

How is cholesterol transported in plasma?

A

In complexes with lipoproteins (synthesised in the liver)

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47
Q

List 4 functions of cholesterol

A

Plasma membranes

Component of bile salts

Precursor for steroid hormones

Myelin (neuron axonal ‘wrapping’)

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48
Q

What is the role of the liver in cholesterol processing (6)?

A

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.

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49
Q

What vitamins and minerals does the liver store?

A

Fat soluble vitamins D E A K

Minerals - iron and copper

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50
Q

What is the main bile pigment?

A

Bilirubin

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51
Q

How is bilirubin formed?

A

From the breakdown of haem in the spleen and bone marrow

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52
Q

Where is bilirubin exported into?

A

Bile

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53
Q

What is conjugated with bilirubin?

Which cell in the liver does this?

What is the purpose of this?

A

Hepatocytes conjugate bilirubin with glucuronic acid to form a polar, water-soluble molecule, which is exported into bile.

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54
Q

When bilirubin is moving through the blood, what is it bound to?

A

Albumin

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55
Q

Once bilirubin has been conjugated and released into the small intestine, what is it broken down into?

How does this get excreted?

A

Urobilinogen

Picked up by the portal vein, then excreted in urine

56
Q

Which blood tests show hepatocyte/hepatitic damage?

A

ALT (alanin transaminase)

AST (aspartate transaminase)

57
Q

Which blood tests show bile duct/obstructive damage?

A

Alkaline phosphotase

Gamma GT

58
Q

Name the 5 true tests of liver function

A

Prothrombin time

Bilirubin

Albumin

Urea/creatinine

pH

59
Q

What causes jaundice?

A

Failure of the body to excrete bile

Clinically apparent when serum bilirubin is twice above normal concentration - 34uM/L

60
Q

In which 3 places can gallstones cause an obstruction?

A

Gallbladder

Bile duct

Major duodenal papillae

61
Q

What are the 3 layers of the wall of the gallbladder?

A

Epithelium

Lamina propria

Fibromuscular layer

62
Q

Which layer of the gallbladder is responsible for contraction?

A

Fibromuscular layer

63
Q

List some facts about gallstones

A

Most are cholesterol based

Associated with high fat diets / hypercholesterolaemia

Can be formed by reduced bile secretion or defective reabsorption of bile salts

64
Q

List some pros and cons to US investigation

A

Pros - simple, non-invasive, widely available

Cons - operator dependent, poor specificity, poor views of pancreas

65
Q

What type of imaging can be used to visualise the biliary system?

A

ERCP

Endoscopic retrograde cholangio-pancreatography

66
Q

List the causes of pancreatitis

A

Idiopathic

Gall stones
Ethanol
Trauma

Steroids 
Mumps
Autoimmune
Scorpion bites
Hypercalaemia/hypertriglyceridaemia
ERCP
Drugs
67
Q

What does the endocrine pancreas secrete?

A

Insulin

Glucagon

Somatostatin

68
Q

What does the exocrine pancreas release?

A

Enzymes

Amylase, trypsin

Chymotripsin, lipase

HCO3-

69
Q

List some symptoms of chronic pancreatitis

A

Pain - epigastric region

Pancreatic failure

Diabetes (endocrine)

Malabsorption (exocrine)

70
Q

What blood results would be raised in biliary obstruction?

A

Bilirubin

Alkaline phosphatase - raised

GGT - raised

71
Q

When taking a history from a pancreas patient, what questions would you need to ask?

A

Alcohol

HTN

Viruses

Farm

Foreign travel

Sexual history

Drugs

72
Q

What are the 2 types of pancreatic cancer?

A

Adenocarcinoma

Neuroendocrine

73
Q

What is a cancer of the bile duct called?

A

Cholangiocarcinoma

74
Q

List some pros and cons to using CT to image the pancreas

A

Pros - widely available, good views of pancreas, transferable images

Cons - radiation exposure, high demand

75
Q

List some pros and cons to using MRCP to view the pancreas

A

Pros - good mapping of ducts

Cons - limited availability

76
Q

List some pros and cons to using MRCP to view the pancreas

A

Pros - good mapping of ducts

Cons - limited availability

77
Q

List some pros and cons to using ERCP to view the pancreas

A

Pros - high sensitivity and specificity

Cons - invasive, technically challenging, complications

78
Q

What are the 4 phases of pharmacokinetics?

A

Absorption

Distribution

Metabolism

Excretion

79
Q

What 3 effects does drug metabolism have on drug activity?

A

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

80
Q

Where do orally administered drugs go after absorption?

A

Portal system to the liver

81
Q

What is ‘first pass metabolism’?

A

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.

82
Q

Which organ is the major site of drug metabolism?

A

The liver

83
Q

In which 2 places are drugs excreted?

A

Bile

Urine

84
Q

What is a phase I drug reaction?

A

Conversion of a drug to an intermediate metabolite by adding a functional group through:

  • oxidation
  • reduction
  • hydrolysis
85
Q

What is the purpose of phase I drug reactions?

A

Increase polarity of the drug

Provide a site for phase II (conjugation) reactions

86
Q

Do phase I reactions make a drug more or less pharmacologically active?

A

Less active

87
Q

In what circumstance would a drug not need to undergo phase I metabolism?

A

If it already has a functional group in its chemical structure

88
Q

What is the purpose of phase II reactions?

A

To conjugate a drug to a metabolite to make it more soluble and more easily excreted from the body

89
Q

Do phase II reactions make a drug more or less pharmacologically active?

A

Less active

90
Q

What is the purpose of phase III reactions?

A

To move conjugated metabolites out of the hepatocytes of the liver where they can be excreted

91
Q

Once a drug has undergone a phase III reaction, where will it go?

A

Larger molecules will be excreted in the bile

Smaller molecules will reach the systemic circulation and be excreted via the kidneys

92
Q

What is the most common type of phase I metabolism reaction?

A

Oxidation of a drug

93
Q

Which enzymes catalyses phase I reactions?

A

Cytochrome P450 enzymes

94
Q

Discuss cytochrome P450 enzymes

What 3 things need to be present for them to function?

A

Haem proteins (haem molecule at active site)

Molecular oxygen
NADPH
NADPH cytochrome P450 reductase

95
Q

What is the mixed function oxidase system?

A

Molecular oxygen

NADPH

NADPH cytochrome P450 reductase

What is needed for cytochrome P450 enzymes to function

96
Q

Describe oxidation of a drug by cytochrome P450 enzymes

A

Involves oxidation and reduction

Catalyses the transfer of one O2 atom to the drug while the other O2 atom is reduced to water

97
Q

What is the most common cytochrome P450 isoform?

A

CYP3A

98
Q

List some phase I reactions that are NOT oxidation by P450

A

Reductions

Oxidation without P450

  • alcohol dehydrogenase
  • monoamine oxidase (NA, 5-HT)

Hydrolytic reactions that occur in the plasma and many tissues
-aspirin

99
Q

What type of chemical reaction are cytochrome P450 enzymes responsible for?

A

Oxidation reactions

100
Q

Describe the role of monamine oxidase in phase I reactions

A

Oxidation of a metabolite without the cytochrome P450 enzymes

Inactivates biologically active amines

  • NA
  • 5-HT
101
Q

A patient lacks cytochrome P450 enzymes.

What phase I reactions will be able to take place?

A

Reductions

Ethanol metabolisiation by alcohol dehydrogenase

Inactivation of NA and 5-HT by monamine oxidase

Hydrolytic reactions

102
Q

Which enzyme metabolises ethanol?

A

Alcohol dehydrogenase

103
Q

Where in the liver are P450 enzymes found?

What else are found here?

A

On the smooth endoplasmic reticulum of hepatocytes

Conjugating enzymes involved in phase II reactions

104
Q

What is bilirubin conjugated with in the liver?

A

Glucuronic acid

105
Q

Which enzyme conjugates glucronide?

A

UDP-glucuronyl transferase

106
Q

What moves hydrophillic metabolites from hepatocytes?

A

Multi-purpose membrane-bound transport carrier systems

107
Q

Give an example of a drug administered as a pro-drug and activated by phase I metabolism

A

ACE inhibitors

108
Q

Which drug, after phase I metabolism, yields a toxic metabolite?

A

Paracetamol

109
Q

What determines the duration of action of digoxin and atenolol?

A

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

110
Q

What considerations need to be made when prescribing drugs to neonates?

A

Hepatic drug-metabolizing enzyme systems are immature.

Renal clearance inefficient

Lower doses of all drugs are needed

111
Q

Why can metabolic clearance be quicker in children?

A

CYPs are mature

Relative liver mass and hepatic blood flow are higher

112
Q

What considerations need to be made when prescribing drugs to children?

A

Dosages of medicines should be obtained from a paediatric dosage handbook.

Prescribed dosages are judged by considering both age and body surface area.

113
Q

What considerations need to be made when prescribing drugs to elderly patients?

A

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

114
Q

During which phase of drug metabolism are drug interactions likely to occur?

A

Phase I reactions

Likely to interact with enzymes e.g. cytochrome P450 enzymes

115
Q

What classes of drugs are CYP3A enzymes responsible for metabolising?

A

Most calcium channel blockers

Most benzodiazepines

Most HIV protease inhibitors

Most HMG-CoA-reductase inhibitors

Cyclosporine

Most non-sedating antihistamines

Oral contraceptives

116
Q

Give some examples of CYP3A inhibitors

A

Fluconazole (antifungal)

Erythromycin (macrolide Abx)

Cimetidine (histamine H2 receptor antagonist)

Grapefruit juice

117
Q

What effect can CYP3A inhibitors have on drug metabolism?

A

Reduced drug clearance

Higher plasma concentrations of drug

Potentially toxic drug levels and adverse effects

118
Q

Give some examples of CYP3A inducers

A

Carbamazepine

Rifampicin

Rifabutin

Ritonavir

St. John’s Wort - herbal remedy for depression

119
Q

What effect can CYP3A inducers have on drug metabolism?

A

Increased clearance of drug

Lower plasma levels of drug

Lack of therapeutic effect

120
Q

Which drugs can St. John’ Wort commonly interact with?

A

Warfarin

Anti-epileptics

Oral contraceptives

121
Q

If someone has low CYP450 activity, what effect will this have on drug metabolism?

A

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

122
Q

If someone has high CYP450 activity, what effect will this have on drug metabolism?

A

More drug inactivation - may require increased dose of drug

More drug activation

  • rapid onset
  • may require reduced dose to prevent accumulation of drug
123
Q

Give an example of a drug that is activated by cytochrome P450 enzymes

A

Codeine

CYP2D6 isoform

124
Q

List 5 side effects of codeine

A

N+V

Light-headedness

Dizziness

Sweating

Constipation

125
Q

List 6 signs of opioid toxicity

A

Respiratory depression

Skeletal muscle flaccidity

Cold and clammy skin

Bradycardia

Hypotension

Constipation

126
Q

What effects will liver cirrhosis have of drug metabolism?

A

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

127
Q

Define bioavailability

A

The proportion of administered drug which reaches the systemic circulation unchanged and is thus available for distribution to the site of action

128
Q

Define first pass metabolism

A

The extent of metabolism occurring BEFORE the drug enters the systemic circulation

129
Q

Which 3 drugs increase in bioavailability in cirrhosis?

A

Calcium channel antagonist - nicardipine

B-adrenoceptor antagonist - propranolol

Calcium channel antagonists - verapamil

130
Q

What will happen to the bioavailability of ramipril in liver cirrhosis?

A

Bioavailability will be reduced - needs first-pass metabolism to activate it

131
Q

What effect will hypoproteinaemia have on drug bioavailability?

A

Leads to reduced drug-binding capacity

More unbound pharmacologically active drug to circulate

132
Q

What 3 things need to be considered when prescribing in liver disease?

A

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

133
Q

If a patient is jaundiced with normal stools and urine, what does this suggest?

A

Pre-hepatic cause of jaundice (high bilirubin)

134
Q

If a patient is jaundiced with dark urine and normal stools, what does this suggest?

A

Hepatic cause of jaundice

Bilirubin has been able to be conjugated and excreted in the urine, causes the darker colour

135
Q

If a patient is jaundiced with dark urine and pale stools, what does this suggest?

A

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.

136
Q

What does prothrombin time assess?

A

The extrinsic pathway of the clotting cascade

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