A5-A6 Drugs in liver disease Flashcards
1
Q
describe the UK Chief Medical Officers’ Low Risk Drinking Guidelines
A
- to keep health risks from alcohol to a low level it is safest not to drink more than 14 units a week on a regular basis
- if you regularly drink as much as 14 units per week, it is best to spread your drinking evenly over 3 or more days
2
Q
describe 1 unit of alcohol
A
- 10 ml of pure ethanol
- amount of alcohol average adult can process in an hour
3
Q
what are withdrawal symptoms?
A
symptoms that heavy drinkers who suddenly decrease or stop drinking altogether may experience
4
Q
state some withdrawal symptoms of alcohol
A
hand tremors
sweating
high HR
nausea and vomiting
headache
loss of appetite
depression or anxiety
irritability
restlessness
insomnia
5
Q
why do withdrawal symptoms from alcohol occur?
A
- alcohol affects the part of our brain that controls fight or flight (our ability to respond)
- drinking suppresses this part of our brain and nervous system
- when drinking stops, we go into fight or flight regardless of danger
6
Q
if alcohol withdrawal is not managed promptly, what risks are there?
A
- risk of seizures, delirium tremens and Wernicke’s encephalopathy
7
Q
5 symptoms of delirium tremens
A
- severe disorientation
- increased HR and BP
- breathing issues
- uncontrollable, aggressive, restless behaviour
- extreme delirium
8
Q
what can alcohol withdrawal cases be complicated by?
A
- mental health illness
- vulnerability
- lack of social support
- other comorbidities
9
Q
what is the NICE guidance for alcohol withdrawal?
A
prescribe a benzodiazepine
- chlordiazepoxide or diazepam
- start with quite high dose and wean off to reduce to zero
- may be given according to symptoms when required if alcohol intake hasn’t been as severe
- at a fixed dose regimen or symptom-triggers regimen
- reducing the dose to zero over 7-10 days
10
Q
what do benzodiazepines do during alcohol withdrawal?
A
suppress the side effects of withdrawal
11
Q
why are patients not sent home with these benzodiazepine drugs?
A
- they have a very high street value and can be sold on for a lot of money
- this is a safety net precaution
- medications suppress bodily functions and can cause drowsiness
- if a patient relapses and drinks alongside medications, you have double the depressive effects and this can cause harm
- we want to avoid potential over-sedation
12
Q
symptoms of Wernicke’s encephalopathy
A
- acute confusion
- psychosis
- ataxia (poor muscle control)
- oculomotor dysfunction (uncoordinated eyes)
13
Q
why does Wernicke’s encephalopathy occur?
A
- due to lack of thiamine (vitamin B1)
- often complication of high alcohol intake
14
Q
for Wernicke’s encephalopathy, describe when the following treatment may be used:
parenteral thiamine followed by oral thiamine
A
should be given to patients:
- with suspected WE
- those who are malnourished or at risk of malnourishment
- those who have decompensated liver disease or who are attending hospital for acute treatment
- given parenterally (IV or IM) if severe
15
Q
for Wernicke’s encephalopathy, describe when the following treatment may be used:
prophylactic oral thiamine
A
- should also be given to harmful or dependent drinkers if they’re in acute withdrawal, or before and during assisted alcohol withdrawal
- can be given after parenteral treatment or if alcohol / malnourishment isn’t as severe
16
Q
for the treatment of Wernicke’s encephalopathy, what is often given alongside the parenteral / oral thiamine?
A
multivitamins
17
Q
Rupert Jeffries (54) has been admitted to hospital for monitored assisted withdrawal from alcohol. His chlordiazepoxide weaning regimen has been prescribed. He has a PMH of alcohol excess and malnourishment.
Suggest a suitable prescription to prevent Wernicke’s encephalopathy
A
- IV thiamine for ‘prophylaxis of Wernicke’s encephalopathy’
- BNF: 1 pair once daily for 5-7 days, deep intramuscular injection into the gluteal muscle
18
Q
state the 8 things measured in an LFT
A
ALT
AST
ALP
GGT
bilirubin
albumin
INR
prothrombin time
19
Q
what are the levels of ALT and AST in LFTs used to detect? what do their levels being raised mean?
A
- damage to hepatocytes (hepatocellular damage)
- raised levels shows damage / liver injury
20
Q
what are transferases and where are they present?
A
intracellular enzymes present in hepatocytes
21
Q
where are hepatocytes present? what is the function of this place?
A
- present in the liver parenchyma
- this is the functional component on the liver (helps to filter blood and remove toxins)
22
Q
what will hepatocytes release when they are damaged?
A
- enzymes AST and ALT
- released when they are injured or damaged
23
Q
what can hepatocytes be damaged by causing them to release AST or ALT?
A
- alcohol
- drug exposure
- a virus (eg. hepatitis)
- non-alcoholic fatty liver disease
24
Q
which of ALT or AST is more specific to the liver? where else is the less specific one found?
A
- ALT is more specific to liver (L for liver)
- AST is also found in the heart, skeletal muscles, pancreas etc.
25
what causes very high levels of ALT (up to several thousand)?
acute injury
26
in which is the level of ALT typically higher: acute injury or chronic hepatitis?
- acute injury
- levels usually not as high in chronic hepatitis (liver function is worse)
- chronic hepatitis means there were fewer hepatocytes to begin with to release AST and ALT
27
what are ALP levels used to detect?
- cholestasis
- when the flow of bile from liver is reduced or blocked (eg. by a gallstone)
28
in cholestasis, where can the blockage be? what can happen if it is not diagnosed? what is it often an indicator of?
- blockage can be in the liver or in the bile duct
- if not diagnosed, bile can start to digest the liver from the inside
- often an indicator of bile obstruction
29
what is bile?
a digestive liquid produced in the liver that flows through the bile duct to where it needs to be
30
why is bile non-specific?
it is also present in bone cells
31
if ALP is raised but it's unclear whether this is due to liver or bone disease, what should happen?
- patient should be looked at in conjunction with other LFT results
- if all LFT is normal but high ALP, bone cancer or other bone issues may be the case
32
how can GGT be used for diagnosis of different conditions from LFTs?
- enzyme released in all types of liver dysfunction (difficult to use for differentiation)
- fairly specific marker though (95% due to liver isoenzyme)
33
diagnose a raised GGT with a raised ALP or bilirubin
cholestatic damage (bile obstruction)
34
diagnose a raised GGT in isolation
alcohol abuse or enzyme-inducing drugs
35
state 2 examples of enzyme-inducing drugs
rifampicin
phenytoin
36
what is bilirubin produced by? explain how
- by the destruction of red blood cells
- red blood cells are produced by bone marrow and have around a 3 month cycle of use before they are replaced again
- when they are broken down they release bilirubin and this travels to the liver for excretion to the kidneys
37
what causes jaundice?
- lack of break down of bilirubin by liver due to liver failure
- causes severe yellowing of skin (jaundice)
38
why is bilirubin non-specific for liver injury?
because it can also be released in haemolytic anaemias
39
what limit of serum bilirubin can produce jaundice in adults?
anything in excess of 50 micromol/L
40
what is jaundice seen in?
- hepatic damage (decreased metabolism of unconjugated bilirubin)
- also seen if a cholestatic cause is likely
41
if a cholestatic cause of increased bilirubin is likely, which other 2 levels in the LFTs would also be raised? what does this indicate?
- ALP and GGT
- indicates post-hepatic obstruction
42
what is the liver responsible for the manufacture of?
- plasma proteins such as albumin
- this is the synthetic function of the liver
43
what is albumin a marker of?
- synthetic function of the liver (because this is where it is made)
- acts as a hepatocellular marker
44
how is albumin non-specific?
- low in malnourished patients or those with nephrotic syndrome
- these people don't have the building blocks they need to do this manufacturing in the first place
45
is albumin an indicator of chronic or acute liver disease? explain how
- albumin has a half-life of around 20 days
- therefore, it is an indicator of chronic liver disease, not acute
46
in what instance is it unusual to see high levels of albumin?
in acute liver injury
47
state the 2 clotting indicators on LFTs
INR
prothrombin
48
what is meant by INR?
- International Normalised Ratio
- ratio of a patient's prothrombin time compared to a control
- warfarin is a vitamin K antagonist
49
what is the liver responsible for producing in regards to clotting? consumption of what food helps with this production?
- vitamin K-dependent clotting factors
- green leafy vegetable consumption helps with this
50
what happens if INR increases in terms of what events could be occurring in the body AND the likelihood of bleeding/clotting?
- synthetic function of liver decreased OR absorption of vitamin K impaired
- more likely to have a blood, less likely to have a clot
51
what could an increased INR be a sign of?
not enough vitamin K or problem with synthetic function of the liver
52
what is the difference between patients with an INR of 1 and 2?
INR of 2 means twice as likely to have a bleed compared to someone with an INR of 1
53
why is INR non-specific?
if the patient on vitamin K antagonist (eg. warfarin) or patient has coagulopathy disorders may also be deranged
54
which changes occur more rapidly: changes in prothrombin time or changes in albumin?
- changes in prothrombin time occur more rapidly
- more useful in predicting hepatocellular damage in acute situations
- prothrombin time is the amount of time it takes for clotting to occur
55
how can giving someone vitamin K help to determine their problem regarding INR and prothrombin time?
- if things improve after a couple of days, it is likely it was an issue with vitamin K absorption
- if things don't improve, it is likely there is an issue with the synthetic function of the liver
56
describe the levels of ALT, AST, ALP and GGT in the pre-hepatic stage
ALT normal
AST normal
ALP normal
GGT normal
57
describe the levels of ALT, AST, ALP and GGT in intrahepatic hepatitis
ALT highest
AST high
ALP normal / mildly high
GGT normal / mildly high
58
describe the levels of ALT, AST, ALP and GGT in the intrahepatic alcohol stage
ALT high
AST highest
ALP normal
GGT high
59
describe the levels of ALT, AST, ALP and GGT in the post-hepatic biliary stage
ALT normal
AST normal
ALP high
GGT high
60
describe the levels of ALT, AST, ALP and GGT in the non-hepatic stage
ALT normal
AST normal
ALP high
GGT normal
61
how long does liver disease have to be to be classified as chronic?
longer than 6 months
62
what are the 4 stages of liver classification from good to worst?
healthy liver
fatty liver
hepatitis
cirrhosis
63
when do we need to intervene with liver patients?
- when a patient has decompensated liver disease (give them vitamin K)
64
what liver related disease will likely kill a patient and requires end of life care?
end stage decompensated cirrhosis
65
what can ascites be used to assess?
the severity of chronic liver disease, but no indication about metabolic capacity
66
what 5 parameters are given a score in the Child-Pugh system?
ascites
encephalopathy
nutritional status
albumin
bilirubin
67
what are the Child-Pugh scores and what do they mean?
- A, B or C
- C represents the most advanced disease
68
some medicines can result in acute liver damage or cholestasis. what must be done if these are prescribed?
- monitoring of liver function s essential with these medicines
- baseline LFTs should be taken and then further monitoring as required
- baselines must be taken so we can determine why raised levels may have occurred
69
what can some medicines result in regarding the liver?
- hepatic enzyme induction or inhibition
- we must be aware of these medicines and take them seriously
70
is liver injury predictable or unpredictable?
can be predictable and dose-dependent OR idiosyncratic
71
what is meant by idiosyncratic in terms of liver injury?
unpredictable, occurs at a lower incidence, no idea why it has happened
72
what should always be considered in a patient with any type of liver damage?
- ALWAYS consider possible contribution of drugs
- there could always be drugs involved
- not just illegitimate drugs that are misused but also standard medicines at standard doses
73
state some drugs that can cause liver damage
amiodarone
azathioprine
carbamazepine
isoniazid
methotrexate
NSAIDs
antibiotics
paracetamol
phenytoin
rifampicin
sodium valproate
statins
74
state 2 examples of antibiotics that can cause liver damage
co-amoxiclav
flucloxacillin
75
what patient factors should be considered when handling drugs in patients with liver disease?
signs and symptoms
LFTs
diagnosis
76
what drug factors should be considered when handling drugs in patients with liver disease?
pharmacokinetics
pharmacodynamics
side effect profile
77
what is the main site of drug metabolism?
liver
78
what drugs are hepatic metabolism the most important for?
- lipid-soluble drugs
- whereas water-soluble drugs are readily renal excreted
79
many medications undergo a multi-stage hepatic metabolic process. how many stages are in this process? explain it
- two-stage hepatic metabolic process
phase I
- involves metabolism (oxidation, reduction, hydrolysis)
- eg. cytochrome P450 enzymes (CYP450)
- affected a lot more than phase II reactions in those with liver disease
phase II
- includes biotransformation with conjugation of the drug or some of its metabolites
- eg. glucuronidation and sulfation
80
which phase of drug metabolism is more affected in liver disease: phase I or II?
- phase I
- CYP-mediated reactions are affected more in liver disease than phase II
- expression of CYP 1A, 2C19 and 3A are decreased in cirrhosis
81
which enzymes' expressions are decreased in cirrhosis?
CYP 1A, 2C19 and 3A
82
what is it important to be aware of in alcoholic liver disease?
the variability in inhibition and induction of metabolism, depending on whether acute or chronic exposure to alcohol
83
does acute ethanol exposure in alcoholic liver disease lead to metabolic inhibition or induction? what does this mean for phase I and II reactions?
- inhibition
- phase I and phase II reactions reduced
84
does chronic ethanol exposure BUT no hepatocellular changes in alcoholic liver disease lead to metabolic inhibition or induction? what does this mean for phase I and II reactions?
- induction
- phase I and phase II are induced
85
does alcoholic cirrhosis in alcoholic liver disease lead to metabolic inhibition or induction?
- inhibition
- similar to non-alcoholic cirrhosis
86
what does a decreased gut motility in cirrhosis mean regarding absorption in pharmacokinetics?
- a delay in gastric emptying
- a reduction in the rate (but not extent) of absorption
87
what liver related issue may result in reduced absorption and bioavailability of a specific type of drugs? what type of drugs is this?
CHOLESTASIS may result in reduced absorption and bioavailability of LIPOPHILIC drugs
88
drugs with what varied parameter may need dose reduction in liver disease and for what reason?
drugs which have a LOW BIOAVAILABILITY due to high first pass metabolism may need dose reduction in liver disease due to an INCREASED BIOAVAILABILITY
89
what does ascites lead to an increase of regarding distribution in pharmacokinetics and what can this lead to?
- increases volume of distribution for water-soluble drugs
- leads to a reduced drug concentration due to increased water
90
give an example of a water-soluble drug whose concentration is altered by ascites
gentamicin
91
what is ascites?
a build-up of fluid in the space between the lining of the abdomen and abdominal organs
92
what can be done to reduce / get rid of ascites?
fluid can be drained
93
what can low albumin levels mean fro certain drugs regarding distribution in pharmacokinetics?
- drugs which are highly protein bound usually are at a higher concentration of free drug
- this can potentially lead to toxicity
- eg. phenytoin
94
what can excess bilirubin cause regarding distribution in pharmacokinetics?
- can displace highly protein bound drugs from their binding sites
- leads to more free drug
95
impaired liver metabolism only occurs when? why is this?
- only occurs in severe disease
- liver tissue has excellent reserves
96
describe the hepatic blood flow in cirrhosis and explain why it is like this
- reduced hepatic blood flow in cirrhosis
- due to portosystemic shunting
- less blood flows through liver and moves to systemic circulation
97
explain hepatic clearance in liver disease and what it causes
- hepatic clearance is reduced
- increases drug levels and toxicity
- this causes issues for drugs with a narrow therapeutic window
98
what drugs may need their dose increasing in liver disease and why?
- prodrugs
- they need to be metabolised to their active form by the liver
99
give an example of a prodrug that may need its dose increasing in patients with liver disease
enalapril (blood pressure medication)
100
what renal parameter can be reduced in patients with severe liver disease? what is this called?
- renal excretion can be reduced
- this is called hepatorenal syndrome
101
what is CrCl?
creatinine clearance
102
explain CrCl in patients with cirrhosis
- may be overestimated in patients with cirrhosis
- reduced serum creatinine if reduced muscle mass and reduced conversion of creatine to creatinine in the liver
103
state 2 circumstances where creatinine clearance will be reduced
- if a drug is excreted in the bile
- if the patient has cholestasis
104
state 6 drug factors to think about in liver disease
- hydrophilic or hydrophobic?
- protein bound?
- does it displace bilirubin? or is it displaced?
- is it metabolised by the liver?
- does it have a high extraction ratio?
- is it potentially hepatotoxic?
105
state 5 common examples of medications you will need to be aware of reducing / avoiding in liver disease
- constipating drugs
- sedating drugs
- drugs that lower seizure threshold
- drugs which increase the risk of GI ulceration and bleeding
- drugs which cause endocrine / metabolic changes
106
what can constipating drugs do in patients with liver disease?
these medicines can cause or worsen constipation and can precipitate or worsen hepatic encephalopathy (HE) in patients with liver disease
107
constipating drugs can cause an accumulation of toxic waste products. how can this be an issue for those with liver disease?
accumulation of toxic waste products can cross the BBB which can cause confusion
108
what is hepatic encephalopathy defined as?
HE is defined as a spectrum of neuropsychiatric abnormalities in patients with liver dysfunction
109
state 3 examples of constipating drugs that should be reduced or avoided in those with liver disease
loperamide
codeine
amitriptyline
110
what medicines can be co-prescribed with constipating medicines for patients with liver disease? what else can this be a treatment for?
- laxatives such as lactulose
- this can also be used to prevent / treat encephalopathy
111
what is the ideal for patients with HE in regards to their toilet habits and why?
- ideally you want those with HE to be producing 2-3 soft stools per day
- this is to clear toxins from the body and prevent confusion from toxins crossing the BBB
112
why should sedating drugs be avoided in patients at risk of HE?
because the brain is more sensitive to sedating effects
113
what 2 symptoms will increase risk or worsen HE?
sedation
confusion
114
what precaution should be taken when handing out sedating drugs to those with liver disease?
say 'if you notice any drowsiness then do let us know'
115
state 3 example sedating drugs to be aware of in those with liver disease
- opioids
- sedating antihistamines
- tricyclic antidepressants (eg. amitriptyline)
116
patients who struggle with excessive alcohol consumption are at an increased risk of what relating to drugs which reduce seizure threshold?
patients who struggle with excessive alcohol consumption are at an increased risk of seizures due to withdrawal
117
state 5 example drugs which reduce seizure threshold in liver disease and should be reduced or avoided
- tramadol
- pethidine
- sedating antihistamines
- antipsychotics
- antidepressants
118
are drugs which reduce seizure threshold contraindicated for those with liver disease?
- no
- they are not never used but we must be aware of their potential effects
119
in which patients do drugs which increase GI ulceration have increased risk?
patients with:
- portal hypertension
- varices
- low platelets
- deranged clotting
120
in those with liver disease, what may already be compromised regarding GI ulceration risk?
- integrity of GI mucosa may already be compromised by excessive alcohol
- leads to increased GI ulceration risk
121
synthesis of what 2 things may be impaired if the integrity of GI mucosa is compromised and in those with liver disease
vitamin K
clotting factor
122
state 4 examples of drugs that increase GI ulceration in liver disease
clopidogrel
warfarin
corticosteroids
SSRIs
123
what drugs are contraindicated in patients with a certain liver effecting disease?
- NSAIDs are contraindicated in those with any degree of liver cirrhosis
124
what side effects can the use of NSAIDs in those with liver cirrhosis cause?
- fluid retention
- electrolyte abnormalities
- GI ulceration and bleeding
- inhibition of platelet aggregation
- reduction in glomerular filtration
125
what can diuretics cause in those with liver disease?
hyponatraemia and hypokalaemia
(encephalopathy)
126
how can NSAIDs lead to worsening ascites and what can this cause?
- NSAIDs can increase sodium and water retention
- leads to worsening ascites
- precipitating renal failure
127
state examples of medicines with a high sodium content
- antacids
- soluble tablets can also precipitate or worsen ascites
128
what are varices? what can happen to them? how are they created?
- expanded / dilated blood vessels that develop most commonly in the oesophagus and stomach
- these can burst
- they are created by portal hypertension
129
in which patients are oesophageal varices more common?
those with cirrhosis
130
when do oesophageal varices develop?
- when blood flow through the liver is obstructed by scarring
- increases the pressure inside the portal vein that carries blood from the intestines to the liver (portal hypertension)
131
what does portal hypertension lead to?
- an increase in the blood pressure inside the veins
- veins expand / dilate under higher pressure resulting in varices which can burst an cause significant bleeding
132
how can oesophageal varices be managed?
- with banding to chop them off and assist healing
- pharmacologically with terlipressin and reducing PV hypertension
133
what can be extremely significant regarding oesophageal varices?
- impaired liver function in terms of clotting
- as well as ruptured varix
134
what is generally thought of regarding patient with pre-existing liver disease?
they are thought to be at no greater risk of drug-induced liver damage than the general population
135
what are the exceptional drugs regarding having no risk to those with pre-existing liver disease?
patients with pre-existing liver disease are thought to be at no greater risk of drug-induced liver damage than the general population
exceptions:
- methotrexate
- rifampicin
136
explain the clearance of paracetamol during liver impairment. relate this to how we prescribe paracetamol to those with liver impairment
- reduced clearance of paracetamol in liver impairment
- we don't tell patients with liver impairment to take 2 tablets QDS
- we caution 3g per day so either 2 tablets 3x a day or 1 tablet 4x a day if being very cautious
137
what does most evidence suggest surrounding paracetamol use in those with liver impairment? state the normal doses for patients
- safe to use in majority of patients with liver disease at normal doses
- weight < 50kg, 500mg QDS max
- weight > 50kg, 1g QDS max
138
in active liver disease, what is the maximum paracetamol dose?
- dose is often more cautionary
- max = 3g per 24 hours
139
what is difficult to predict regarding paracetamol use in those with liver disease?
- overdose risk
- as little as 10 tablets in 24 hours can cause liver toxicity in a patient at high risk of liver damage
- some patients can take lots of paracetamol and be absolutely fine
140
how long does it take for paracetamol overdose symptoms to onset?
- onset is often later than expected
- usually 3-4 days later
141
what are often the early features of paracetamol overdose?
- nausea and vomiting
- these usually settle
142
when is liver damage maximal after a paracetamol overdose and what can this lead to?
- maximal 3-4 days after overdose
- may lead to encephalopathy, haemorrhage and death
143
what should be given within 24 hours of paracetamol overdose and how?
- acetylcysteine protects the liver if given within 24 hours (ideally 8 hours)
- it is given as an IV infusion
144
how can patients needing paracetamol overside treatment be identified?
- by measurement of plasma-paracetamol concentration related to time
145
how is acetylcysteine given after paracetamol overdose and what does it do?
- given as 3 IV infusions (varied doses)
- given over 21 hours
- should protect the liver from any damage
146
state patients that are at high risk of liver damage
- those of low body weight
- those that are malnourished
- those who take enzyme-inducing drugs
- those who have drank alcohol
147
state some of the roles of pharmacists in supporting patients with liver disease
- identification and prompt referral of suspected liver disease
- identifying possible drug causes of liver disease
- review patients LFT results and interpret their meaning
- recommend dosage / frequency / drug changes in liver disease
- guideline development
- Public Health and signposting
- management of overdose (eg. paracetamol)
