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Block 1 AR > Liver and gallbladder > Flashcards

Liver and gallbladder Flashcards

1
Q

What 4 factors can affect the livers ability to metabolise drugs?

A

Age
Liver disease
Genetic constitution
Drug interactions

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2
Q

Why should the initial dose of a drug prescribed to an elderly person be lower than for a normal adult?

A

Relative liver mass and hepatic blood flow are reduced so reduced clearance

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3
Q

What should you try to do with polypharmacy?

A

Rational prescribing - try to minimise the total number of drugs that the patient is taking

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4
Q

Why might children need a higher dose than adults for certain drugs?

A

Metabolic clearance of the drugs is faster due to mature CYPs and relatively large liver mass and hepatic blood flow

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5
Q

What do phase 1 reactions do to a drug in the liver?

A

Add a functional group to make it more reactive and therefore provide a site for phase 2 reactions

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6
Q

Which is the most common phase 1 reaction?

A

Oxidation

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7
Q

Which family of enzymes are largely responsible for oxidation reactions in the liver?

A

Cytochrome P450

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8
Q

What 3 things do cytochrome P450 enzymes require to function?

A

Oxygen, NADPH and NADPH cytochrome P450 reductase

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9
Q

What do phase 2 reactions do to a drug in the liver?

A

Add a large molecule to make it more water soluble and therefore easier to excrete. Also tend to inactivate it. Conjugation

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10
Q

Which drugs are more likely to be excreted via the bile?

A

Highly ionised or large molecules >500 Da

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11
Q

What are multi drug resistance proteins?

A

Efflux transporters for removing drug metabolism products from hepatocytes

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12
Q

Give 4 reasons why patients with liver disease are at risk of toxic drug effects at low doses

A

Reduced functioning of hepatocytes/reduced number to metabolise
Decreased plasma binding proteins so increased bioavailability
If portal hypertension - reduced first pass metabolism and shunting of drug back into systemic circulation
Increased susceptibility to hepatotoxic drugs

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13
Q

What happens in paracetamol induced liver injury?

A

Overdose of paracetamol causes a saturation of phase 2 enzymes so more phase 1 reactions occur. This causes an accumulation of NAPQBI which is toxic to hepatocytes. At first, glutathione inactivates this toxic product but once it runs out, liver damage occurs.

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14
Q

What would you use acetylcysteine and methionine for?

A

As antidote to paracetamol overdose as they increase liver synthesis of the cytoprotective glutathione

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15
Q

How can genetics affect people taking codeine?

A

Some people have low levels of CYP2D6 which is responsible for converting the codeine prodrug into morphine. Codeine itself is a very weak analgesic so patients report little pain relief with many side effects

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16
Q

Why is it important to ask about herbal remedies eg St. John’s wort when taking a history?

A

Drug interactions
St. John’s wort induces CYP3A and so leads to increased metabolism of drugs such as oral contraceptives, benzodiazepines and warfarin. This reduces their bioavailability

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17
Q

List 5 functions of the liver

A 
Energy metabolism
Production of plasma proteins
Synthesis, storage and secretion of bile
Drug metabolism 
Immune functions
Cholesterol processing
Excretion of bilirubin
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18
Q

What are Kupffer cells?

A

Immune cells of liver
Present in sinusoids attached to endothelial cell lining
Ingest bacteria and inflammatory mediators

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19
Q

What 5 types of plasma proteins are made by the liver?

A 
Binding proteins - albumin
Carriage proteins - thyroid binding globulin
Clotting factors - fibrinogen
Pro hormones 
Apolipoproteins
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20
Q

What are the 6 components of bile?

A 
Bile salts
Bile pigments
HCO3
Cholesterol
Lecithin
Trace metals
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21
Q

Which enteric hormone acts to increase bile production of liver?

A

Secretin

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22
Q

What do cholangioctyes secrete and where are they?

A

Lining bile duct, secrete HCO3 and water

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23
Q

What 4 things are bile salts involved in?

A

Elimination of cholesterol
Emulsification of fats in SI so available to pancreatic lipases
Facilitates absorption of fat soluble vitamins
Prevention of cholesterol precipitation in gallbladder

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24
Q

What are primary bile acids conjugated with to form bile salts?

A

Taurine

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25
Q

What are primary bile acids made from?

A

Cholesterol

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26
Q

During recycling of bile salts from terminal ileum, what do bacteria do?

A

Deconjugate bile salt to bile acid

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27
Q

Which 2 bile components are taken from the blood?

A

Bile pigments

Trace metals

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28
Q

What are bile pigments?

A

Excretory products being disposed of by liver via gut

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29
Q

What is bilirubin?

A

Bile pigment formed by breakdown of haem in spleen and bone marrow. Transported in blood by albumin

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30
Q

What does glucuronyl transferase catalyse?

A

Conjugation of drugs and bilirubin with glucuronic acid

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31
Q

What 4 things is cholesterol used for?

A

Plasma membranes
Producing steroid hormones
Formation of bile acids
Myelin

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32
Q

What do lipoprotein complexes transport in the blood?

A

Cholesterol

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33
Q

What is different about zone 1 and zone 3 hepatocytes within a lobule?

A

Zone 1 specialised in oxidative metabolism, gluconeogenesis and urea synthesis
Zone 3 specialised in drug metabolism, glycolysis and lipogenesis

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34
Q

What lies in centre of each lobule in liver?

A

Central vein

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35
Q

What are vascular spaces between plates of hepatocytes called?

A

Sinusoids

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36
Q

What 3 cell types are found in sinusoids?

A

Endothelial
Kupffer
Lipocytes

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37
Q

What happens to lipocytes when things go wrong in liver?

A

They differentiate and fibrose

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38
Q

How many functionally independent segments does the liver have?

A

8

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39
Q

Describe the blood supply to the liver

A

2 sources: Portal vein (70%) & hepatic artery (30%)

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40
Q

Where does the hepatic artery run?

A

In free edge of lesser omentum

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41
Q

Describe the blood supply to the gallbladder

A

Right hepatic artery branches into cystic artery

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42
Q

Describe the branching of the common hepatic artery

A 
Branches from coeliac trunk
Gastroduodenal branches from here
Changes into hepatic
Branches into left and right hepatic
Right hepatic branches into cystic
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43
Q

What vessels contribute to forming the portal vein?

A

Splenic vein
Super mesenteric vein
Inferior mesenteric vein

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44
Q

Where would you find the fundus of the gallbladder?

A

9th costal cartilage, L1

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45
Q

What vessels join to form the bile duct?

A

Common hepatic and cystic ducts

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46
Q

Where does the bile duct drain into?

A

Major duodenal papilla

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47
Q

What is Murphys sign?

A

Acute cholecystitis

Palpate, pain on inspiration. Patient will stop breathing in

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48
Q

Where does gallbladder pain referral cover?

A

Right hypochondrium
Right shoulder - diaphragm irritation
Epigastrium

49
Q

How much blood flows into the liver?

A

25% of cardiac output

1.5L/min

50
Q

What is the splanchnic circulation?

A

Includes blood flow through the stomach, small intestine, large intestine, pancreas, spleen and liver
Portal vein carries venous blood draining from all of these organs except the liver itself

51
Q

What are the functional units of the liver called?

A

Lobules

52
Q

What is each lobule of the liver arranged around?

A

Central vein

53
Q

Describe the organisation of a liver lobule

A

Plates of hepatocytes, lying in a cage of reticuloendothelial cells
The plates are separated by vascular spaces called sinusoids
Blood from the sinusoids converges on the central vein
In turn, the central veins converge on the hepatic vein
The reticuloendothelial cell meshwork includes diverse cell types:
Endothelial cells, Kupffer cells, lipocytes (stellate cells)

54
Q

What processes of energy metabolism is the liver involved in?

A 
Glycogenolysis 
Gluconeogenesis 
Glycogen synthesis 
Glycolysis, citric acid cycle and fatty acid synthesis
Lipid metabolism 
Ketogenesis 
Triglyceride synthesis from fatty acids 
Protein metabolism 
Deamination 
Urea formation
55
Q

What plasma proteins does the liver synthesise?

A

Major plasma proteins - albumin
Factors involved in haemostasis/ fibrinolysis: coagulation e.g. fibrinogen, coagulation inhibitors e.g. a1-antitrypsin, fibrinolysis e.g. plasminogen
Carriage proteins (binding proteins) e.g. transferrin, sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG)
Pro-hormones
Apolipoproteins

56
Q

How much bile does the liver secrete each day?

A

0.7-1.2L per day

57
Q

What is the man function of the gallbladder?

A

Storage and concentration of bile

58
Q

What effect does secretin have on the liver and pancreas?

A

Stimulates bile production

Stimulates HCO3 secretion from pancreas

59
Q

What effect does CCK (cholecystokinin) have on the gallbladder and pancreas?

A

Gallbladder contraction to release bile

Enzyme secretion from pancreas

60
Q

What are bile salts and what do they do?

A

Bile acids conjugated with taurine or glycine

Solubilise fat in small intestine

61
Q

Which components of bile are secreted by hepatocytes into bile canaliculi?

A

Bile salts
Cholesterol
Lecithin
Bile pigments

62
Q

What do cholangioctyes secrete?

A

Bicarbonate

Water

63
Q

What are primary bile acids formed from?

A

Cholesterol

64
Q

Where do secondary bile acids come from?

A

Recycled from entero hepatic circulation from terminal ileum back to liver

65
Q

Of the bile salts that are recycled back to the liver, what can happen to them?

A

Recycled intact - 75%
Deconjugated by bacteria in terminal ileum to form primary bile acids, some are dehydroxylated to secondary bile acids - 25%

66
Q

How much cholesterol comes from our diet and how much is synthesised in the body?

A

15% diet

85% synthesised

67
Q

What do hepatocytes do to bilirubin to aid its excretion?

A

Conjugate it with glucuronic acid to form a polar water soluble molecule which is exported into bile

68
Q

Describe the excretion process of bilirubin

A 
Taken into liver via sinusoid from blood
Conjugated with glucuronic acid
Excreted into bile canaliculus 
Excreted into small intestine
Converted to urobilinogen by bacterial proteases 
90% excreted in faeces
10% excreted via kidneys
69
Q

What is a portal triad?

A

Portal arterioles
Portal venule
Bile duct

70
Q

What occurs with a filter failure of the liver?

A

Portal hypertension

71
Q

What happens with an elimination failure of the liver?

A

Jaundice

72
Q

What occurs with metabolic failure of the liver?

A

Acidosis
Muscle loss
Coagulopathy
Hepato renal syndrome

73
Q

What is hepatic encephalopathy?

A

Failure of elimination, filter and metabolism of the liver
Confusion, altered level of consciousness, coma
Hallmark of liver failure
Caused by ammonia and other toxins build up

74
Q

What do LFTs test for?

A

ALT/AST - hepatocyte damage

Alk Phos/gamma GT - bile duct damage

75
Q

What are some true tests of liver function?

A 
Prothrombin time
Bilirubin (excretion)
Albumin
Urea/Creatinine
pH
76
Q

What can cause decompensation in chronic liver disease?

A 
Infection
Toxins - inc alcohol
Trauma - inc surgery
Drugs - sedatives 
Variceal bleed
Dehydration - diuretics 
Malignant transformation - hepatoma
77
Q

What are main causes of liver injury?

A

Fat
Alcohol
Virus
Iron

78
Q

What is jaundice?

A

Failure of body to excrete bile

Clinically apparent when serum Bilirubin is twice above the normal concentration ~ 34uM/L

79
Q

What are the medical terms for gallbladder and bile duct stones?

A

Gallbladder stones - cholelithiasis

Bile duct stones - choledocolithiasis

80
Q

What does the wall of the gallbladder consist of?

A

Epithelium
Lamina propria
Fibromuscular layer

81
Q

What are 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
Pigment stones found in those with Haemolytic disorders (high serum bilirubin levels)

82
Q

What techniques can be used to see gallstones?

A

Ultrasound

ERCP - endoscopic retrograde cholangio pancreatography

83
Q

What is laproscopic cholecystectomy?

A

Keyhole removal of the gallbladder

84
Q

What are 4 causes of metabolic liver injury?

A

Alcohol
Haemochromatosis
Wilson disease
Alpha1 anti trypsin deficiency

85
Q

What are 3 inflammatory causes of liver injury?

A

Autoimmune hepatitis
Primary biliary cirrhosis
Primary sclerosing cholangitis

86
Q

What are 4 types of non alcoholic fatty liver disease?

A

Fatty liver
Non alcoholic steatohepatitis
Cryptogenic cirrhosis
Liver cancer

87
Q

What are 3 types of phase 1 reaction?

A

Oxidation
Reduction
Hydrolysis

88
Q

Where are cytochrome p450 enzymes located?

A

On smooth ER

89
Q

What 2 types of cytochrome p450 exist?

A

Constitutive - present all the time

Inducible - synthesised in response to appropriate stimulus

90
Q

What are cytochrome p450s?

A

Haem proteins

91
Q

What is the mixed function oxidase system?

A

Molecular oxygen, NADPH and NADPH cytochrome P450 reductase Combination of factors required for functioning of cytochrome p450 enzymes

92
Q

What occurs during oxidation of a drug by cytochrome p450 enzymes?

A

Cytochrome P450 catalyzes the transfer of one oxygen atom to the substrate while the other oxygen atom is reduced to water

93
Q

Give an example of a drug metabolised by a reduction reaction

A

Inactivation by warfarin by CYP2A6

94
Q

Give examples of oxidations that do not involve the P450 system

A

Ethanol is metabolized by alcohol dehydrogenase (cytosolic enzyme)
Monoamine oxidase inactivates many biologically active amines (e.g. noradrenaline, 5-HT)

95
Q

Give examples of hydrolytic reactions which metabolise drugs

A

Hydrolytic reactions are not restricted to the liver and occur in plasma and in many tissues. Aspirin (acetylsalicylic acid) is hydrolyzed to salicylic acid

96
Q

Which chemical groups most often involved in conjugate formation?

A

Glucuronyl, acetyl, methyl, sulphate and glutathione

97
Q

Name 2 drugs whose rate of action is determined by their renal excretion rather than liver metabolism

A

Digoxin

Atenolol

98
Q

Give an example of a drug which is activated by liver metabolism

A

ACE inhibitors - activated by esterases

Diamorphine to morphine

99
Q

What factors affect drug metabolism?

A 
Age
Genetics
Drug interactions
Environmental influences
Liver disease
100
Q

Describe the effect of age on drug metabolism

A

Neonates - low doses required as hepatic enzymes are immature and renal clearance is inefficient
Children - Metabolic clearance quicker in children because CYPs are mature and relative liver mass and hepatic blood flow are higher
Dosages of medicines should be obtained from a paediatric dosage handbook. Prescribed dosage judged by age and body surface area
Elderly - capacity for drug metabolism, particularly phase I is reduced because the relative liver mass and hepatic blood flow are lower. Polypharmacy is common. Start drug treatment with the smallest
effective dose. Rational prescribing to minimize the number of drugs

101
Q

What is polymorphic distribution?

A

A trait that has differential expression in >1% of the population

102
Q

Which drugs inhibit metabolism by CYP3A and therefore reduce clearance of calcium channel blockers, benzodiazepines, HIV protease inhibitors, HMG-CoA-reductase inhibitors, Cyclosporine, non-sedating antihistamines and oral contraceptives?

A

-azole antifungal drugs e.g. fluconazole
macrolide antibiotics e.g. erythromycin
cimetidine – a histamine H2 receptor antagonist
grapefruit juice

103
Q

Give examples of CYP3A inducers which increase clearance of many drugs

A 
Carbamazepine   anti-convulsant 
rifampicin  antibacterial 
rifabutin   antibacterial 
ritonavir  antiviral 
St. John’s Wort
104
Q

Which drugs should not be taken with St. John’s wort due to it inducing activity of CYPs and therefore increasing clearance of these drugs?

A

Warfarin
antiepileptics
oral contraceptives

105
Q

What is bioavailability?

A

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

106
Q

What is first pass metabolism?

A

Orally-administered drugs, which are usually absorbed in the small intestine, reach the liver via the portal circulation. At this stage the drugmay be extensively metabolized

107
Q

Why is bioavailability of drugs increased in liver disease?

A

Drug metabolising capacity is reduced where hepatocytes are either sick or reduced in number
Hepatocytes that metabolise drugs are by-passed when portal-to-systemic shunts develop in cirrhosis - reduced first pass metabolism
Hypoproteinaemia leads to reduced drug-binding capacity which allows more unbound and pharmacologically active drug to circulate

108
Q

Name 3 drugs whose bioavailability is increased in liver disease

A

Nicardipine - calcium channel antagonist
Propranolol - b-adrenoceptor antagonist
Verapamil - calcium channel antagonist

109
Q

Name a drug that requires first pass activation

A

ACE inhibitors

110
Q

Name drugs which are highly protein bound and therefore their pharmacologically active dose will be much greater in liver disease

A

Diazepam (benzodiazepine sedative)
Tolbutamide (hypoglycaemic sulphonylurea)
Phenytoin (anticonvulsant)
Valproic acid (anticonvulsant)

111
Q

At what dose can paracetamol be lethal?

A

2/3 times maximum therapeutic dose

112
Q

In paracetamol induced liver injury, what is hepatotoxicity caused by?

A

Accumulation of toxic metabolite NAPBQI

113
Q

In paracetamol-induced liver injury, how soon after overdose does fatal hepatocellular necrosis occur?

A

48-72 hours

114
Q

Who is particularly at risk of paracetamol overdose?

A

Patients taking P450-inducing drugs inc alcohol and St. John’s wort
Patients with glutathione depletion e.g. patients with eating disorders

115
Q

What are functions of the liver?

A 
Carbohydrate/lipid/protein metabolism
Processing dead red blood cells
Cholesterol/phospholipid/lipoprotein production
Immune function
Bile production and secretion
Drug metabolism/detoxification
Vitamin storage
Steroid hormone production
Plasma protein production
116
Q

Why do gallstones cause dark urine and pale stools?

A

Pale stools occur as no bilirubin reaches the gastrointestinal tract and dark urine results from reflux of conjugated bilirubin into blood which is excreted in the urine

117
Q

Explain how varices are formed

A

Portal hypertension causes back up of blood into systemic circulation. At points of anastamoses, vessels under high pressure and swell up. In the oesophagus, these varices are delicate and can rupture easily

118
Q

Which veins form the portosystemic anastamoses responsible for forming caput medusae in portal hypertension?

A

Para umbilical veins - portal

Superior and inferior epigastric veins - systemic

Block 1 AR (19 decks)

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