11 Hepatic Flashcards
(351 cards)
1
Q
What are the two part of a simple emulsifier molecule?
A
Hydrophilic head and hydrophobic tail
2
Q
An emulsifier molecule is a ________
A
Amphiphile
3
Q
What is an amphiphile?
A
Has a lipophilic portion and a hydrophilic portion
4
Q
What is bile?
A
A dark green-to-orange fluid produced by the liver which helps the digestion of lipids in the SMALL INTESTINES
5
Q
Where is bile stored and discharged?
A
Stored in the gallbladder and is discharges in the duodenum
6
Q
What are the main functions of the liver?
A
Metabolic & synthesis
7
Q
What are the lobes of the liver and what separates them?
A
Left and right
Joined by a ligament (Falciform and round)
8
Q
How many segments are there in the liver?
A
8
9
Q
Describe how blood enters the liver
A
- Hepatic artery 25% - oxygenated from circulation
- Hepatic portal vein 75% - deoxygenated from the small intestines (ascending & descending colon)
10
Q
Describe how blood leaves the liver
A
Hepatic vein into the IVC back towards the heart.
11
Q
How does bile leave the liver?
A
Leaves via hepatic ducts to the gallbladder
12
Q
What are sinusoids?
A
Low pressure vascular channels receiving blood from terminal branches of the hepatic artery and vein
13
Q
What are sinusoids lined with?
A
Endothelial cells and flanked with plates of hepatocytes
14
Q
Where do hepatocytes receive plasma from?
A
Small intestine
15
Q
Where does nutrient rich plasma collect from the small intestines?
A
In the space of Disse and flows back towards portal tracks collecting in lymphatic vessels
16
Q
What are Kupffer cells?
A
A type of macrophages that ingest foreign particles and other cells
17
Q
What are the fat-soluble vitamins?
A
A, D, E, K, B12 and folic acid
18
Q
Beside metabolic and synthetic, what other functions does the liver have?
A
- Immunological
- Storage of fate soluble vitamins
- homeostasis of glucose
- production of bile
- clearance of medication, toxins and bilirubin
19
Q
Describe carbohydrate metabolism in the liver
A
It is one of the most important functions of the liver and with the pancreas, tightly controls blood glucose levels.
After a meal, your blood glucose levels increase and a large amount is stored as glycogen, other sugars are also converted and lots of intermediate products are formed form carbohydrates.
20
Q
What is the process that converts starch into glucose?
A
Gluconeogenisis
21
Q
How is glucose levels sensed in the liver?
A
- Glycogen phosphorylase - in the presence of glucose is able to be activated
- This then releases the hormone PP1
- PP1 converts glycogen synthase B into the active form
- Glycogen synthase B is then able to covert glucose into glycogen to be stored
22
Q
Describe some of the functions of the liver when it comes to protein synthesis
A
- deamination of amino acids
- interconversions of the various amino acids and synthesis of other compounds from amino acids
- removal of ammonia from the liver, can become toxic in the body. High levels can lead to hepatic encephalopathy
- formation of urea
- produce plasma proteins
- able to interconvert other amino acids
23
Q
Why would we want to remove ammonia?
A
Produces by the bacteria in the gut
Toxic in high levels
Think about patients who cannot remove ammonia –> hepatic encephalopathy (brain dysfunction due to liver damage)
24
Q
What would the liver not working mean for clotting factors?
A
The liver synthesises vitamin-K-dependant clotting factors
If not able to carry out function, the liver won’t produce as much of these clotting factors
This would result in the patient having increased risk of bleeding
25
What would happen if patient is unable to produce bile salts in regard to vitamin K?
Vitamin K is fat soluble
If patient is unable to produce bile salts, fat cannot be emulsified well
Thus much reduced absorption of vitamin K
26
Where is albumin produced?
Liver
27
What is albumin?
Major plasma protein and is involved in drug transportation and other protein bound components such as bilirubin
28
What would happen if a patient was low in albumin?
Water leaves out of the vascular space --> oedema or ascites
29
What is oncotic pressure?
Oncotic pressure is the pressure exerted by large molecules in the blood, such as proteins, that pulls fluid back into capillaries.
30
What is bile made up of?
Bile salts, cholesterol, phospholipids, bile pigments, electrolytes and water
31
What are bile pigments?
Excretory products of the liver
32
What is bilirubin?
Breakdown product of haemoglobin and is conjugated by the liver
33
Where is bilirubin excreted?
Normally excreted in the faeces and gives the appearance of brown
34
What would problems in the liver or bilirubin system result in?
A building up of bilirubin in the blood —> jaundice and lightening of the stools - less pigments
35
What makes up most of bile?
H2O (97%)
36
What is the responsibility of reticuloendothelial cells (macrophages)?
Responsible for the maintenance of blood
37
How do reticuloendothelial cells maintain blood?
- take up red blood cells and break down haemoglobin into HAEM and GLOBIN
- globin is further broken down into amino acids
- haem is broken down into iron and biliverdin
- biliverdin is reduced to produce bilirubin
38
What catalyses haem —> iron & biliverdin?
Haemoxygenase
39
What reduces biliverdin to bilirubin?
Biliverdin reductase
40
Bilirubin + albumin?
Where does this occur?
Bilirubin-albumin
Vasculature
41
Unconjugated bilirubin binds to what?
Albumin in the bloodstream
42
Glucuronic acid is added to ______ to form _______
1. UDPGT
2. UDPGT1A1
43
What is the main form of conjugated bilirubin?
Bilirubin digluconide
44
Where is conjugated bilirubin excreted?
Into the duodenum in the bile into the stools
45
What does colonic bacteria do?
Removes the glucuronic acid resulting in urobilinogen
46
How much of urobilinogen is reabsorbed as part of hepatic circulation?
Roughly 20%
47
What happens to urobilinogen?
It is further oxidised to produce stercobilin and excreted in faeces giving colour
48
What happens to reabsorbed urobilinogen?
Carried to the liver and either recycled for bile production or reaches the kidneys
49
What is Gilbert’s syndrome?
Slower metabolism of bilirubin due to reduced levels of glucuronyl transferase leading to elevated unconjugated bilirubin levels
50
What are bile caniculi?
Small duct network between hepatocytes that collect bile and eventually merge into bile ducts, forming the common hepatic duct.
51
Describe the pathway between bile caniculi to the gall bladder
Bile caniculi —> bile ducts —> common hepatic duct —> cystic duct —> gall bladder
52
What two ducts lead to the common bile duct?
Cystic duct and common hepatic duct
53
What are the constituents of bile?
Bile acid-dependent and bile acid-independent
54
What makes bile acid-independent constituents of bile?
Made by ductal cells lining the bile ducts
55
What do hepatocytes secrete?
Bile acids, bile pigments and cholesterol
56
Where do both dependent and independent components of bile enter?
They enter intrahepatic bile ducts which drain into the biliary tree
57
What is the biliary tree?
A series of ducts that transport bile from the liver to the gallbladder and duodenum
58
How does the gall bladder concentrate bile?
By removing the water and ions
59
What processes occur in phase I metabolism?
Oxidation, reduction and hydrolysis
60
What processes occur in phase II metabolism?
Glucuronidation, gluthione conjugation, acetylation and sulphation
61
What processes occur in phase III metabolism?
Active elimination
62
Give examples of hormones does the liver catabolises
- insulin
- glucagon
- oestrogens
- glucocorticoids
- growth hormones
63
Why is the liver being an important site for drug and alcohol metabolism significant?
Fat soluble drugs are converted to water-soluble to facilitate excretion into bile or urine
64
At a steady rate, define the rate of elimination of a substance/drug?
The rate of presentation of the drug to the liver (I.e. blood flow) and the rate of exit of the drug from the liver
65
What is the equation for clearance of the liver?
Cl = Q x E
Q - blood flow
E - rate of exit of the drug from the liver
66
What are high extraction ratio drugs?
Drugs that are highly first-pass metabolism
(You lose most of the drug before it even reaches circulation)
67
Why is high extraction drugs an issue with people with reduced blood flow?
Less drug is metabolised there for more active drug will enter circulation
Hepatic blood flow reduced = bioavailability increased
68
Give examples of high extraction ratio drugs
Propranolol, morphine and sertraline
69
What does hepatic clearance depend on?
Blood flow
70
What would you need to alter when giving high extraction ratio drugs to patients with reduced hepatic blood flow?
Alter the dose and dose interval to avoid an accumulation of the drug
71
Describe the enterohepatic recirculation of bile
Bile is continuously produced but is only needed during and after meals. The gallbladder concentrates bile by removing water and ions.
72
Describe the metabolism of bilirubin.
- Unconjugated bilirubin is transported to the liver bound to albumin.
- Glucuronic acid is added to unconjugated bilirubin by UDPGT, forming conjugated bilirubin, primarily bilirubin diglucuronide.
- Conjugated bilirubin is excreted in bile.
- Colonic bacteria deconjugate bilirubin, producing urobilinogen.
- Urobilinogen is oxidised to stercobilin (giving faeces their colour) and partially reabsorbed.
- Reabsorbed urobilinogen is either recycled or reaches the kidneys, where it's oxidised to urobilin and excreted in urine.
73
Summarize the phases of liver metabolism (including Phase III).
Phase I: Oxidation, reduction, hydrolysis.
Phase II: Glucuronidation, glutathione conjugation, acetylation, sulphation.
Phase III: Active elimination
74
Describe the breakdown of haemoglobin and the formation of bilirubin.
Reticuloendothelial cells (macrophages) break down red blood cells, separating haemoglobin into haem and globin. Globin is broken down into amino acids, while haem is converted to iron and biliverdin by haemoxygenase. Biliverdin is then reduced to bilirubin by biliverdin reductase.
75
What factors can reduce hepatic blood flow?
Cirrhosis.
Portal vein thrombosis.
Cardiac failure.
Shock (very low BP).
Portal systemic shunting.
76
What does it mean for a drug to be 'free' in the bloodstream, and how does this relate to albumin?
A non-bound drug is considered 'free' and able to elicit an effect. Drugs that are highly protein-bound bind to albumin for transportation, so only the unbound portion is free to act.
77
What might happen if two drugs with high protein binding are taken together?
This could lead to competitive binding for the binding sites on albumin.
The drug with a higher affinity for albumin would displace the other, increasing the amount of the displaced drug that is 'free' in the bloodstream. This can lead to an increased effect and potentially higher risk of side effects from the displaced drug.
78
What are low extraction ratio drugs?
Low extraction ratio drugs are drugs that are not highly metabolised on their first pass through the liver.
79
What is the impact of reduced hepatic blood flow on the bioavailability of low extraction ratio drugs?
If hepatic blood flow is reduced, the bioavailability of low extraction ratio drugs is not affected, except for drugs that are highly protein bound.
80
What is the main factor that determines the metabolism of low extraction ratio drugs?
The metabolism of low extraction ratio drugs is dependent on the functional capacity of the liver.
81
What happens to the elimination and half-life of low extraction ratio drugs when the functional capacity of the liver is reduced?
If the functional capacity of the liver is reduced, the elimination of low extraction ratio drugs from the systemic circulation is delayed, and their half-life is prolonged.
82
What adjustments might be necessary to the dose interval of low extraction ratio drugs in patients with reduced liver function?
In patients with reduced liver function, it may be necessary to adjust the dose interval of low extraction ratio drugs
83
Give two examples of low extraction ratio drugs.
Citalopram and theophylline.
84
What are the two main patterns of liver damage?
Cholestatic and hepatocellular
85
What is cholestatic liver damage?
Disruption of the flow of bile from the liver. Bile builds up in the biliary tree and the liver.
86
What are the two classifications of cholestatic liver damage?
Intrahepatic and extrahepatic
87
Give some examples of intrahepatic cholestatic liver damage.
- Primary biliary cholangitis
- Certain drugs
- Inflammation of the bile ducts
88
Give some examples of extrahepatic cholestatic liver damage.
- Inflammation of the bile ducts
- Gallstones
- Strictures
89
What is hepatocellular liver damage?
Injury to the hepatocytes
90
What are some causes of hepatocellular liver damage?
- Toxins, such as alcohol or medicines
- Viruses
- Other infections
91
What is steatosis?
An accumulation of fat within the hepatocytes. Can be seen on a microvascular and a macrovascular scale
92
What is hepatitis?
Inflammation within the liver. Can be acute or chronic
93
Define acute hepatitis
History of onset of symptoms should be less than 6 months
94
List the categories of acute hepatitis.
- Hyperacute (within 7 days)
- Acute (within 8-28 days)
- Subacute (within 28-72 days)
95
Define chronic hepatitis.
Symptoms that persist for longer than 6 months.
Generally associated with cirrhosis which can be defined as compensated and decompensated.
96
Describe the progression of damage to the liver.
From a healthy liver (F0) to a cirrhotic liver (F4)
97
What causes damage to the liver?
- Viral causes
- Alcohol
- Drug use
98
What is fibrosis?
Persistent, and extensive hepatic damage leads to active deposition of collagen and formation of scar tissue.
99
What is cirrhosis?
Consistent damage further collagen deposition and scar formation leading to irreversible damage.
100
What are the results of cirrhosis?
- Disruption to the blood flow into the liver
- Erratic regeneration of the liver leading to nodules and irregular surface of the liver
101
How are patients with cirrhosis defined?
Compensated or decompensated. Decompensated cirrhosis will present with features of complications.
102
What is the most common method pharmaceutical companies use to classify the degree of impairment of the liver?
The Child’s Pugh scoring system.
103
What is the disadvantage of the Child’s Pugh scoring system?
It is difficult to pinpoint a really clear set of instructions. Two people with the same Child’s Pugh score could have very different presentations of their liver disease.
104
Give examples of how two people with the same Child’s Pugh score could present differently.
- One person might have ascites which could affect drug distribution.
- Another person could be encephalopathic which results in higher blood brain barrier permeability and increased central effect.
105
List some investigations that might be used to assess liver damage
- Liver Ultrasound
- Computerised tomography (CT scan)
- Endoscopic Retrograde Cholangio-pancreatography (ERCP)
- Magnetic Resonance Cholangiopancreatography (MRCP)
- Magnetic Resonance Imaging (MRI)
- Ultrasound elastography (Fibroscan)
- Liver Biopsy
- Calculate MELD or UKELD Model for End-Stage Liver Disease or UK Model for End-Stage Liver Disease
106
List some signs and symptoms of decompensated liver disease.
- Jaundice
- Ascites
- Unexplained bruising and bleeding
- Varices
- Encephalopathy
- Abdominal pain
- Pale stools and dark urine
- Gynaecomastia
- Fatty stools
- Spider naevi
- Finger clubbing and pruritus
107
Define jaundice.
A term used to describe the yellowing of the skin and the whites of the eyes caused by a build-up of bilirubin in the blood and tissues of the body.
108
What is clinical jaundice defined as?
Serum bilirubin above 50micromol/L
109
What are some common signs of jaundice?
- Yellowing of the skin, eyes and mucus membrane
- Pale-coloured stools (faeces)
- Dark-coloured urine
110
List the three main types of jaundice.
Pre-hepatic, intra-hepatic and post-hepatic.
111
What is pre-hepatic jaundice?
Disruption before the bilirubin has been transported from the blood to the liver caused by conditions such as sickle cell anaemia or other haemolytic conditions.
112
What is intra-hepatic jaundice?
Disruption inside the liver. Can be caused by cirrhosis with reduced hepatocyte function to conjugate bilirubin, or Gilbert’s Syndrome where there is a slower metabolism of bilirubin due to reduced levels of glucuronyl transferase.
113
What is post-hepatic jaundice?
Disruption that prevents the bile from draining out of the gallbladder and into the digestive system caused by conditions such as gallstones or tumours.
114
What is ascites?
An accumulation of fluid within the peritoneum that can be very painful and uncomfortable for the patient.
115
What are some causes of ascites?
- Albumin levels
- Fluid retention
116
What is the first-line treatment for ascites?
Fluid restriction, usually 1.5L daily, but sometimes much more aggressive restriction, and sodium restriction.
117
What is the second-line treatment for ascites?
Adding in diuretics, such as spironolactone and furosemide.
118
What is a potential problem with using diuretics to treat ascites?
Patients sometimes struggle with the diuretic burden
119
What are some cautions associated with the use of diuretics to treat ascites?
- Lowers blood pressure.
- Lowers sodium and can increase/lower potassium levels.
- Side effects of dizziness and increased urination.
120
What is the third-line treatment for ascites?
- Paracentesis
- TIPS procedure
121
When would a patient be considered for a third-line treatment for ascites?
If they are not tolerating diuretics, they would be classed as diuretic resistant.
122
What is the mortality rate for diuretic resistant ascites?
25-50% mortality rate within 12 months
123
What is a paracentesis?
A needle is inserted into the abdomen to drain fluid.
124
What must be done when performing a paracentesis?
Maintain adequate circulating volume with colloids, albumin and potentially terlipressin.
125
What should be given for every 2L of fluid drained during a paracentesis?
100mL albumin. Normal saline should be avoided as this will just accumulate back in the abdomen.
126
What are the risks associated with a paracentesis?
- Infection
- Increased risk of varices or other bleeding
127
What is the main purpose of a paracentesis?
To relieve pressure. It is not a long-term fix.
128
What does TIPS stand for?
Transjugular intrahepatic portosystemic shunt
129
Describe how portal hypertension affects blood flow before a TIPS procedure.
Portal hypertension causes blood flow to be forced backward, causing veins to enlarge and varices to develop across the oesophagus and stomach from the pressure in the portal vein. The pressure backup also causes the spleen to enlarge.
130
Describe how blood flow is affected after a TIPS procedure.
The shunt allows the blood to flow normally through the liver to the hepatic vein. This reduces portal hypertension and allows the veins to shrink to a normal size, helping to stop variceal bleeding.
131
What must be monitored in patients with ascites?
- Daily U&Es – especially sodium, potassium, and creatinine
- Daily weight – aim for 0.5-1kg/day loss
- Fluid chart – note fluid restriction, urine output
132
What should be avoided in patients with ascites?
High sodium preparations (e.g. soluble preparations)
133
What are some complications associated with ascites?
- Dilutional hyponatraemia
- Hepatic Encephalopathy (HE)
- Hepatorenal Syndrome (HRS)
- Gynaecomastia
- Hyperkalaemia
- Muscle cramps
- Spontaneous Bacterial Peritonitis (SBP)
134
What is Spontaneous Bacterial Peritonitis (SBP)?
Infection of the ascitic fluid without an intra-abdominal source of sepsis
135
Where does SBP usually originate?
75% from gut, 25% from skin
136
What is the neutrophil count in SBP?
> 250 cells per mm3
137
What is the mortality rate associated with SBP?
~40%
138
What medications can be used to treat SBP?
- 3rd gen cephalosporins
- Co-amoxiclav
- Tazocin
139
What medications can be used as prophylaxis for SBP?
Norfloxacin / ciprofloxacin
140
What is hepatic encephalopathy (HE)?
Brain dysfunction. Can occur in acute or chronic liver disease. Classified into 4 main clinical grades.
141
What are the main theories for the cause of HE?
Accumulation of toxins
Increased BBB permeability
Increased levels of neurotransmitters
142
What are some potential precipitating factors of HE?
Increased protein load
Reduced ammonia secretion
Electrolyte imbalance / disturbance
Infections
Dehydration
Drugs
143
What are some conditions with similar symptoms to HE?
Hypoglycaemia
Alcohol intoxication
Alcohol withdrawal
144
How is ammonia produced?
From dietary amino acids and by catabolism of amino acids, amines, nucleic acids, glutamine and glutamate (nitrogenous wastes) in peripheral tissues (especially skeletal muscle).
145
How do gastrointestinal micro-organisms contribute to ammonia production?
They convert dietary amino acids and urea into ammonia in the gastrointestinal system.
146
What happens to ammonia after it is absorbed into the portal circulation?
It is taken up by the liver and converted, via the urea cycle, into urea.
147
What happens to urea after it is produced in the liver?
It is excreted into the gastrointestinal system and into the urine.
148
What proportion of ammonia is shunted into the urea cycle?
80-90%
149
What happens to the ammonia that is not shunted into the urea cycle?
The remaining 10-20% is metabolised by peripheral tissues, including the kidney, heart, and brain.
150
What is asterixis?
Also known as liver flap, it is a tremor of the hand when the wrist is extended, sometimes said to resemble a bird flapping its wings.
151
What are the treatment options for HE?
Lactulose
Rifaximin
Metronidazole
Neomycin
Sodium benzoate
152
What is the aim of lactulose treatment?
2-3 loose stools per day
153
How does lactulose work?
Promotes growth of beneficial micro-organisms
Reduces gut protein load
Lowers colonic pH which discourages ammonia producing bacteria
154
When are enemas used in HE treatment?
When the patient is constipated
155
What is the standard dose of rifaximin for HE?
550mg twice daily
156
Describe the properties of rifaximin.
Semi-synthetic rifamycin derivative that is poorly absorbed resulting in reduced systemic side effects.
It is broad-spectrum with activity against aerobic and anaerobic, gram positive and negative organisms.
157
How does rifaximin work?
Binds to the β-subunit of bacterial DNA-dependent RNA polymerase resulting in inhibition of bacterial RNA synthesis
Reduces gut bacteria that would produce ammonia, reduces absorption of ammonia from intestinal lumen
158
When should rifaximin not be used?
In acute infection
When patient on broad-spectrum antibiotics
159
What is portal hypertension caused by?
Increased resistance to flow due to:
1. Disruption of hepatic architecture
2. Compression of hepatic venules by regenerating nodules
160
What is the effect of collateral vessels forming?
They enable blood to bypass the liver.
161
What is a serious complication of portal hypertension?
Variceal bleed.
162
What is the mortality rate associated with variceal bleeds?
50% index bleed
30% for subsequent bleeds
163
What is the mechanism of action of terlipressin in treating variceal bleeds?
Increases the tone of vascular and extravascular smooth muscle cells. The increase in arterial vascular resistance leads to decrease of splanchnic hypervolemia. The decrease of the arterial blood supply leads to reduction of pressure in the portal circulation.
164
Describe the properties of terlipressin.
Synthetic analogue of vasopressin which acts on 3 vasopressin receptors
Greater selectivity for V1 and longer half-life
165
What is the effect of V1a receptor activation?
Very potent splanchnic vasoconstriction (also liver gluconeogenesis, platelet aggregation and release of factor VIII)
166
Describe the biphasic action of terlipressin.
Immediate vasoconstriction effect
Prolonged effect with transformation of terlipressin in-vivo to lysine vasopressin
167
What is the standard dose of terlipressin?
1-2mg every 4-6 hours, continued until haemostasis achieved
168
What should be monitored when administering terlipressin?
Blood pressure
Sodium
Potassium
Fluid balance
169
What are some side effects of terlipressin?
Headaches
Abdominal cramps
Ischaemia
170
Describe the properties of octreotide.
An analogue of somatostatin, a hormone involved in blood vessel tone in the GI tract.
171
What is the mechanism of action of octreotide?
Inhibits splanchnic vasodilatation which decreases splanchnic hypervolaemia. This results in decreased arterial blood supply leading to reduction in pressure in the portal circulation.
172
What has research shown about the efficacy of somatostatin and its analogues vs. placebo in variceal bleeds?
Generally unimpressive data. An analysis of 21 RCTs showed no significant difference in mortality or failure to stop bleeding/re-bleeding, though it did show improvement in initial haemostasis.
173
What treatment is recommended by SIGN guidelines for variceal bleeds?
Terlipressin
174
What has research shown about the efficacy of band ligation vs. sclerotherapy for variceal bleeds?
A meta-analysis showed band ligation was superior in terms of re-bleeding and mortality.
175
What is the recommended treatment for oesophageal variceal (OV) haemorrhage?
Band ligation
176
What are some complications of band ligation?
Technical difficulties
Oesophageal ulceration
177
Describe sclerotherapy for treating variceal bleeds.
Injection of sclerosants (“glue”) e.g. cyanoacrylate.
178
What are some complications associated with sclerotherapy?
Oesophageal ulceration
Sepsis
179
What is the recommended treatment for gastric variceal (GV) haemorrhage?
Sclerotherapy
180
Describe the use of balloon tamponade for variceal bleeds.
It is a temporary measure (< 24 hours) that applies mechanical “pressure” over bleeding points. Several different types are available, e.g. Sengstaken-Blakemore tube.
181
Describe the efficacy of balloon tamponade.
Highly effective when deployed, but high rates of re-bleed when deflated.
182
What are some complications associated with balloon tamponade?
High complication rates e.g. oesophageal ulceration
183
Why is antibiotic use important after a variceal bleed?
Infection is common after upper GI bleed in cirrhotic patients, with 20% of patients developing an infection within 48 hours. Infection is a major cause of mortality and morbidity.
184
What type of antibiotic treatment should be given to patients after a variceal bleed?
All patients should receive broad-spectrum antibiotic prophylaxis.
185
What has research shown about the use of antibiotics vs. placebo after a variceal bleed?
6 RCTs have shown that 7 days of antibiotics decreases mortality
186
What antibiotic treatment is recommended for patients after a variceal bleed?
IV broad spectrum antibiotic (e.g. Tazocin) or meropenem/ciprofloxacin for penicillin-allergic patients.
187
What should be considered in secondary prevention of portal hypertension?
Reducing pressure in the portal vein to reduce the risk of further variceal bleeds which could lead to death. A non-selective beta-blocker such as propranolol or carvedilol may be considered.
188
What are the effects of beta-blockers on portal hypertension?
Splanchnic vasoconstriction (beta2 blockade)
Cardiac output results in reduced portal pressures (beta1 blockade)
189
What are the benefits of beta-blockers in portal hypertension?
Prevent re-bleeding
Increase survival
190
What are the disadvantages of nitrates in portal hypertension?
Problems with tolerability
Dose titration and monitoring
191
What is pruritus usually associated with?
A build up of bilirubin, which is an irritant.
192
List some medication options for treating pruritus.
Colestyramine
UDCA (ursodeoxycholic acid)
Chlorpheniramine
Hydroxyzine
Loratadine
Cetirizine
Rifampicin
Ondansetron
Naltrexone
Naloxone
Sertraline
193
List some non-medication options for treating pruritus.
Calamine lotion
Menthol 2% in aqueous cream
194
What is a micelle?
A sphere of surfactant particles with hydrophilic heads that face polar solvents and hydrophobic tails that face non-polar solvents
195
Where is bile stored?
in the gallbladder
196
Where is bile discharged into?
the duodenum
197
Primary bile acids can go on to make what?
A range of bile salts and acids
198
Bile acids are derivatives of 1. ____ synthesized in the 2.______
1. Cholesterol
2. Hepatocyte
199
When bile salts are protonated they are what?
More fat soluble and act as emulsifiers - for fat soluble vitamins and drugs
Unconjugated --> acid form
200
What happens when bile salt are deprotonated?
They are more water soluble/dispersible as needed in the gut
conjugated --> base form
201
Bile acids are based around the _____ _____
cholesterol skeleton
202
What doe s LogP measure?
How hydrophilic or hydrophobic a molecule is
203
What does a high LogP value mean? e.g >3
Water insoluble/hydrophobic
204
What does a low LogP value mean? e.g <3
Water binder/hydrophilic
205
How is bile modified as it flows through the bile ducts?
by the addition of watery, bicarbonate-rich secretions from the ductal epithelial cells
206
What are the symptoms of gallstones (choledocholithiasis)?
- pain
- jaundice
- dark urine
- pale stools
- itching
- nausea
- vomiting
207
What are gallstones?
hardened pieces of bile that form in the gallbladder of bile ducts
208
What causes the formation of gallstones?
the result of the processes that all cholesterol to precipitate from solution in bile
209
Bile acids have what action on particles of dietary fats and what happens?
Detergent action where they cause fat molecules to be emulsified into droplets - micelles
210
How does emulsification aid absorption of fats?
It increases the surface area making it available for surface adhesion by hydrolytic lipases
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Where do bile salt anions tend to aggregate?
around droplets of fat to form complex bile-stable emulsions
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negatively charged outer droplet surface, formed by bile salt anions, prevent what?
fat droplets coated with bile from flocculating into larger fat droplets
213
Where are triglycerides from micelles absorbed?
The villi on the intestine walls
214
Where are triglycerides from micelles transferred across?
across the intestinal membrane - fats and their constituents are absorbed into the lymphatic system
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What would happen to most of the lipids if there were no bile salts?
The lipids would be excreted in faeces
216
Describe the LogP of fat soluble vitamins
High LogP thus fat soluble
217
Where would fat soluble and dispersible drugs be delivered and why?
Orally in the GIT because they can be absorbed easily via fat using bile
218
Where is fat soluble drugs internalised?
1. in the bile micelle itself
2. in the bile acid emulsified-oil droplet
219
What is vitamin K?
transparent, yellow-orange viscous, odourless oil and is INSOLUBLE in water
220
When would you inject vit.k?
Injection is recommended for preventing and treating vitamin K deficiency bleeding (VKDB) in
infants.
221
What is the formulation of vit K injections?
emulsions
222
What role does bile salt serve?
A dispersing agent
223
Define pharmacokinetics
the study of how the body absorbs, distributes, metabolises, and eliminates a drug.
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What are the key concepts of pharmacokinetics?
ADME
Absorption, Distribution, Metabolism and Excretion
225
What is meant by pharmacodynamics?
describes the effects of the drug on the body
226
What are the key concepts of pharmacodynamics?
- receptor binding
- dose-response relationship
- therapeutic window
227
What is mean by absorption?
the process by which a drug enters the bloodstream
228
What are some of the factors influence absoption?
- drug formulation (linking to the route of administration)
- pH
- presence of food
229
What is meant by bioavailability?
the proportion of the drug that enters the systemic circulation
230
What factors may effect distribution?
- blood flow to tissues
- protein binding
- volume of distribution (Vd)
231
What is meant by Volume of distribution?
describes how extensively a drug spreads into body tissues.
232
what does it mean when drugs have a high Vd?
they are widely distributed into tissues e.g diazepram
233
What does it mean when drugs have a low Vd?
They stay mostly in the blood such as gentamicin
234
What is metabolism?
the process where drugs are chemically modified usually to make it easier to eliminate them
235
Where is the primary site of drug metabolism?
The liver although other organs can contribute
236
What are the key phases of metabolism?
Phase I & II reactions
237
What occurs in phase I reactions?
-oxidation
-reduction
-hydrolysis
Mediated by enzymes such as CYP450 and the reaction introduces a reactive group to the drugs molecule
238
What occurs in phase II reactions?
conjugation reactions where the drug or its metabolites are coupled with another substance to increase it solubility for excretion
239
What are the factors that influence metabolism?
- Genetic variability - CYP450 enzyme activity varies between people
- Drug interaction - some drugs can inhibit/induce CYP enzymes
240
What is excretion?
The process at which the body removes the drug either unchanged or as metabolites
241
Where does excretion primarily occur?
Kidneys via urine but also can occur through bile, sweat or breath
242
What factors influence elimination?
- renal function
- half life
- clearance
243
How can renal function influence excretion?
Impaired kidney function can reduce drug clearance, requiring dose adjustments
244
What is half life?
The time it takes for the drug concentration to decrease by half.
This determines dosing intervals and the time to reach steady state.
245
what is meant by clearance?
The volume of plasma from which the drug is completely removed per unit of time.
Drugs with high clearance (e.g., morphine) need frequent dosing.
246
Describe the shape of CYP450 structure
Fe2+ is coordinated with 4 porphyrin nitrogens
247
Why does CYP450 have an iron center?
It can exist in other forms due to being a transition metal. It can accept or release electrons
248
What determines the isoforms of CPY450?
Variations of the protein
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What are the main 5 CYP isoenzymes?
1A2, 2C9, 2C19, 2D6, 3A4/5
250
Different isoenzymes have different _____
specificities
251
What can inhibit/induce to differing extents CYP specificity?
different agents
252
What are the types of drug-drug interactions?
Pharmacodynamic interactions & Pharmacokinetic interactions
253
What would happen if patient took drugs that inhibit CYP450?
they can fit in the CYP 460 enzyme
Blocking active site and not being metabolized
Thus drug that is normally metabolized by the CYP450 will not.
254
Describe pharmacokinetic interactions in drug drug interaction
one drug affects:
- the plasma concentration
- half-life,
or both, of another drug by altering its **absorption, distribution, metabolism, or elimination**
255
What is induction?
P450 can be affected by drugs and other chemicals.
In response to a chemical, more of an enzyme can be
produced. This is called INDUCTION. increasing expression of CYP450
256
What is inhibition?
P450 can be affected by drugs and other chemicals. Alternatively, less of an enzyme may be produced as a result of INHIBITION. decreasing expression of CYP450
257
What is autoinduction?
Chemicals can induce CYPs to promote their own metabolism
- They may also induce CYPs to promote the
metabolism of other drugs
258
drug A induces CYP450 enzymes so more is induced. would it cause an interaction with drug B?
Potentially:
1. if the enzyme inactivated drug B, and you increase the production of that enzyme you will lower the drugs B leading to treatment failure
2. if the enzymes activate drug Band if you increase the enzyme this, you will get more of drug B being activated and more active metabolites/agents, leading to overdose
259
How does CPY enzyme activation happen?
- ligand dependant nuclear receptors mediates the transcription of CYP
- Drug molecules may activate these receptors and increase the level of transcription from a CYP gene
- More mRNA> more protein > increased metabolism
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what is meant by the net result of the effect of enzyme induction?
is always the increased metabolism of drugs processed by that CYP
261
Why is the time course important for the net result of the effect of enzyme induction?
- what’s the half-life of the drug
- how long does induction take, etc
262
Therapeutic impact depends on whether the drug is a _____
Prodrug
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what does CYP1A1 do?
Binds and oxidises planar aromatic substances
264
What does CYP1A1 induce?
Induced by exposure to polycyclic aromatic hydrocarbons (PAH)
265
where are high levels of CYP1A1 and why is this a risk?
Lungs of smokers
This enzyme metabolises some aromatic to carcinogens which make smokers have a higher risk of lung cancer
266
What does CYP2B metabolise?
Metabolises mephenytoin, cyclophosphamide, some
coumarins, methadone
267
What induces CYP2B6?
Induced by rifampicin, phenobarbitone
268
What is special about CYP3A4?
Metabolises ~50% of drugs in use
269
What can inhibit or induce CYP3A4?
- Other drugs
– Grapefruit juice
270
drug A inhibits CYP450 enzymes so enzyme function is reduced. would it cause an interaction with drug B?
1. if drug b is inactivated, it levels will go up causing overdose
2. if it activate drug B there is higher level of active for causing treatment failure
271
How does enzyme inhibition happen? [3 marks]
1. Some chemicals compete for the same CYP = competitive inhibition
2. Some chemicals have the capacity to destroy CYPs
3. Some chemicals form inactive complexes with CYPs
4. Reduce the amount of CYP
272
What is CYP2D6 responsible for?
Responsible for >70 drug oxidations
273
What would happen if you take statins (eg lovastatin) whilst CYP3A4 is inhibited?
- side effect of statins is *rhabomyolysis* (muscle break down)
274
What is the function of P-glycoprotein?
responsible for pumping the drugs into or out of the cells or urine
275
What are the clinically significant drug-drug interactions between potent CYP3A4 inhibitors and statins?
Increase serum concentrations of statins
Risk of rhabdomyolysis - rapid breakdown of skeletal muscle leading to kidney failure and electrolyte disturbances
276
what is the impact of antibiotics on the gut flora disrupts the enterohepatic circulation of oestrogens?
- oestrogen in the pill is metabolised inn the liver when it is conjugated so it can put into bile
- then enter small intestines where the bacteria there can deconjugate it
- reassembling it so it can be reabsorbed to carry out its effects again
- intrahepatic cycle
**antibiotic disrupts this by killing the bacteria in the small intestines**
277
What is pharmacogenomics?
The study of how genes affect a person’s response to drugs
278
What does genetic variation influence?
- Pharmacokinetics (what the body does to the drug)
– Pharmacodynamics (what the drug does to the body)
279
What is drug gene pairing?
Increasing number of drug-gene pairs in which awareness of genetic variation can impact prescribing
280
What are the pharmacogenomics priority areas?
* Pharmacogenomic test guided therapy
* Targeted treatment based on genotype
* Chimeric antigen receptor (CAR) T-cell therapy
* Advanced therapy medicinal products (ATMP)
* Tissue agnostic drugs
281
What is polymorphisms?
The presence of two or more variant forms of a specific DNA sequence that can occur among different individuals or populations
282
What are the types of gene mutations?
* Missense mutation (SNP)
* Nonsense mutation (SNP)
* Insertion
* Deletion
* Duplication
* Frameshift mutation
283
What is a Missense mutation (SNP)?
Replacement of a single nucleotide
284
What is a Nonsense mutation?
type of genetic change that causes a stop sign to appear in the middle of a sentence within the genetic code.
285
What is an insertion mutation?
Insertion of a single nucleotide
286
What is a deletion mutation?
a type of mutation that involves the loss of one or more nucleotides from a segment of DNA.
287
What is a duplication mutation?
a type of genetic mutation that involves the replication of a section of DNA.
In this process, an extra copy of a gene or a segment of DNA is created, leading to an altered genetic sequence.
288
What is a frameshift mutation?
A frameshift mutation in a gene refers to the insertion or deletion of nucleotide bases in numbers that are not multiples of three.
289
What CYP enzymes are involved in metabolism of enzymes that have polymorphism?
CYP2D6, CYP2C19 andCYP2C9
290
What is the action of CYP2D6 on codeine?
metabolises codeine
291
What is the action of CYP2C19 on clopidogrel?
activates
292
What is the action of CYP2C9 on warfarin?
breaks down and metabolises
warfarin has a narrow therapeutic index
293
Why would you want to look at CYP2C19 for drug gene pairs for testing?
for antiplatelet therapy following ischemic stroke
294
polymorphisms of CYP2C19 would cause what?
CYP 2C19 loss of function alleles have a reduced capacity for clopidogrel bioactivation
this would reduce the amount of active clopidogrel metabolite
295
What are the different types of polymorphism for CYP2D6?
Ultrarapid metabolizer
Normal metabolizer
Intermediate metabolizer
Poor metabolizer
296
Describe codeine
Nonsynthetic opioid and is selective agonist of the μ-opioid receptor – Weak affinity
297
What is the function of codeine?
Functions as a prodrug with active metabolites
– Morphine (10x more potent on μ receptor)
– Codeine-6-glucuroinide
298
How is codeine converted into morphine?
via CYP 2D6
299
What is the implication of CYP 2D6 polymorphisms for codeine therapy in patients that are ultra rapid metabolizers?
* Increased formation of morphine
* Higher risk of toxicity
* high risk of respiratory depression
300
What is the implication of CYP 2D6 polymorphisms for codeine therapy in patients that are normal metabolizers?
Expected formation of morphine
301
What is the implication of CYP 2D6 polymorphisms for codeine therapy in patients that are intermediate metabolizers?
* Reduced morphine formation
* If no response consider other medications
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What is the implication of CYP 2D6 polymorphisms for codeine therapy in patients that are poor metabolizers?
* Greatly reduced morphine formation
* Insufficient pain relief
* Avoid codeine consider another opioid
303
What are the adverse effects of codeine
* Drowsiness
* Light-headedness, Dizziness
* Sedation
* Shortness of breath
* Nausea, Vomiting
* Sweating
* **Respiratory depression**
304
Gemfibrozil is a drug used in the treatment of
hypercholesterolaemia. It is a potent inhibitor of CYP2C8. What would happen if this drug was administered to a patient who was taking the antidiabetic drug, pioglitazone, which is a substrate for CYP2C8?
The plasma concentration of pioglitazone would increase
305
Patient is taking grapefruit. Is it an inhibitor or activator of CYP3A4?
inhibitor of CYP3A4
306
What enzymes metabolises alcohol?
ADH - alcohol dehydrogenase
ALDH - aldehyde dehydroygenase
307
What does ADH and ALDH metabolise alcohol into?
acetate
308
How does acetate leave the body?
As carbon dioxide and water
309
What is the 'microsomal ethanol-oxidising system'?
An alternative pathway breaking down alcohol when there is a high level of alcohol in the blood.
310
What is Alcoholic steatohepatitis? [2 marks]
Advance stage of fatty liver disease caused by heavy alcohol disease where there is an accumulation of fat + hepatocellular injury (inflammation and fibrosis)
311
What are examples of mechanisms of injury to the liver resulting in Alcoholic steatohepatitis?
- oxidative stress
- acetaldehyde accumulation
- altered protein function
312
How can Alcoholic steatohepatitis improve?
With abstinence of alcohol although a proportion of patients will develop cirrhosis despite being abstinence
313
What are the risk factor of liver damage due to alcoholic steatohepatitis?
* sex - women> men
* obesity
* genetic factors
* race and ethnicity
* binge drinking
314
In blood results , what examples would you look at to diagnose Acute alcoholic hepatitis?
Bilirubin, ALP, AST, GGT and INR
315
What are some symptoms of withdrawal of alcohol?
* marked tremour
* fear and delusions
* fever
* rapid pulse
* dehydration
* seizures
316
What is the first line medication for alcohol withdrawal syndrome?
Treated with combination sedatives and vitamin supplementation
Chlordiazepoxide + Pabrinex
317
Why would you prescribe Chlordiazepoxide for alcohol withdrawal syndrome?
* Long half life
* Sedative and anti-convulsant properties
* Slower onset action – low dependence forming potential
318
When would you give benzodiazepram in alcohol withdrawal syndrome?
For seizures
319
What would you get issues with lack of vitamins due to high intake of alcohol?
* Vitamin deficient due to poor diet
* Malabsorption in the intestinal mucosa
* Thiamine deficiency - polyneuritis with motor and sensory defect
* Wernicke’s encephalopathy
* Korsakoff’s – permanent
320
How can abstinence be achieved in Acute alcoholic hepatitis?
* Psychological treatments
* Pharmacological treatments
* Combination of both
321
list drugs that can be used in Acute alcoholic hepatitis for abstinence
- Acamprosate
- disulfiram
- naltrexone
322
How does disulfiram aid abstinence of alcohol?
Irreversibly inhibits acetaldehyde dehydrogenase therefore leading to increased levels of acetaldehyde
323
What is Metabolic-associated fatty liver disease?
Formerly known as non-alcoholic fatty liver disease (NAFLD), metabolic-associated fatty liver disease (MAFLD) is a new definition of liver disease.
* Known metabolic dysfunction
324
What contributes to the prevalence of metabolic-associated fatty liver disease?
- sedentary behaviour
- low physical activity
- high calorie intake relative to exposure
325
When is diagnosis of metabolic-associated fatty liver disease made?
It is made generally in people with confirmed hepatic steatosis and at least one of the following:
**TOE**
T - Type II diabetes mellites
O - overweight/obesity
E - Evidence of metabolic dysregulation in lean individuals
326
What are the contributing factors it metabolic-associated fatty liver disease?
- Genetics
- Insulin resistance
- Glucotoxicity
- Lipotoxicity
- Oxidative stress
- Mitochondrial dysfunction
327
Why are obese individuals at an increased risk of metabolic associated fatty liver disease?
due to increased visceral adipose tissue which can lead to insulin resistance and hyperinsulinemia enhancing adipose lipolysis
328
How does high carbohydrate or high fat diets contribute to the development of hepatic steatosis?
Via glucotoxicity and Lipotoxicity.
- Large carbohydrate intake can lead to high glucose levels which is harmful to hepatic cells
329
How would you manage metabolic-associated fatty liver disease?
Adopting a healthy lifestyle in the main way:
- lose weight
- eat a healthy diet
- have water instead of sweet drinks
- exercise regularly
- stop smoking
330
What is viral hepatitis?
an infection that causes liver inflammation and damage. There are different viruses that cause hepatitis, including hepatitis A, B, C, D, and E
331
What are the types of viral hepatitis?
Includes A B C D E
332
Describe how hepatitis A &E is spread
Typically spread through contact with **food or water that has been contaminated by an infected person’s stool**.
People may also get hepatitis E by eating undercooked pork, deer, or shellfish.
333
What does hepatitis A & E cause?
only **acute, or short-term, infections**.
In an acute infection, your body is able to fight off the infection and the virus goes away
334
How is hepatitis B C & D spread?
Spread through contact with an **infected person’s blood**.
Hepatitis B and D may also spread through contact with other body fluids. This contact can occur in many ways, including **sharing drug needles or having unprotected sex**
335
What can hepatitis B C &D cause?
can cause acute and chronic, or long-lasting, infections
336
When does chronic hepatitis occur?
Chronic hepatitis occurs when your body isn’t able to fight off the hepatitis virus and the virus does not go away
337
What complications can chronic hepatitis lead to?
- cirrhosis
- liver failure
- liver cancer link
338
What can prevent or lower your chances of developing complications because of chronic hepatitis?
Early diagnosis and treatment of chronic hepatitis can prevent or lower your chances of developing these complications
339
What is acute hepatitis B?
Short term infection
340
How long can symptoms last in acute hepatis?
Symptoms can last weeks, up to 6 months
341
What would increase your chance if developing chronic hepatitis B?
Chance of developing chronic hepatitis B is greater if you were infected with the virus as a young child
342
How common is HBV
More common in some other parts of the world
343
Who are more likely to have HBV? give some examples [3 marks]
* are infected with HIV, because hepatitis B and HIV spread in similar ways
* have lived with or had sex with someone who has hepatitis B
* have had more than one sex partner in the last 6 months or have a history of sexually transmitted disease
* are men who have sex with men
* are injection drug users
* work in a profession, such as health care, in which they have contact with blood, needles, or body fluids at work
* live or work in a care facility for people with developmental disabilities
* have diabetes
* have hepatitis C
* have lived in or travel often to parts of the world where hepatitis B is common External link
* have been on kidney dialysis
* live or work in a prison
* had a blood transfusion or organ transplant before the mid-1980s
344
Discuss the issue with reactivation of hepatitis B
In people who have ever had hepatitis B, the virus may become active again, or reactivated, later in life.
When hepatitis B is reactivated, it may start to damage the liver and cause symptoms.
Reactivated hepatitis B can lead to acute liver failure
345
Who are the people at risk for reactivation of hepatitis B? [3 marks]
- take hepatitis C medicines
- have HIV infection
- take medicines that reduce the activity of the immune system, such as chemotherapy
346
What must be done before starting treatments for hepatitis B?
as part of routine screening the patient would would need past exposure to HBV testing and if positive then prophylactic HBV treatment would need to be considered.
347
What are some symptoms of hepatitis B?
* dark yellow urine
* feeling tired
* fever
* gray- or clay-coloured stools
* joint pain
* loss of appetite
* nausea
* pain in the abdomen
* vomiting
* yellowish eyes and skin, called jaundice
348
What are the possible causes of hepatitis B?
* being born to a mother with hepatitis B
* having unprotected sex with an infected person
* sharing drug needles or other drug materials with an infected person
* getting an accidental stick with a needle that was used on an infected person
* being tattooed or pierced with tools that were used on an infected person and weren’t properly sterilized, or cleaned in a way that destroys all viruses and other microbes
* having contact with the blood or open sores of an infected person
* using an infected person’s razor, toothbrush, or nail clippers
349
What are the antiviral treatments of hepatitis B?
Tenofovir
Entecavir
Lamivudine
350
What is the function of antiviral treatments of hepatitis B?
the agents are used to suppress replication of the HBV virus.
There is currently no ‘curative agent’ for the treatment of HBV.
351
