DILI Flashcards
What are the types of DILI caused by drugs
Inflammatory changes - hepatitis
fatty changes- steatosis
hepatocyte necrosis and death
bile duct injury- cholestasis
disruption of transport proteins
covalent binding of drug to P450 enzyme
cirrhosis - scarring of liver
liver tumours
What is type A drug induced liver injury
Example: Paracetamol toxicity
can affect all people
dose dependent and predictable
short latency period- lasts hours to weeks
What is type B induced liver injury (IDIOSYNCRATIC)
-in susceptible individuals
-its unpredictable and non-dose dependant
-due to hypersensetivity
-lasts from 5-90 days
How is injury caused by drugs
-may be direct liver toxicity
-injury due to drug itself or metabolite
-idiosyncratic reaction
in normal drug metabolism how does Phase 1 reaction occur?
-oxidative pathway by Cytochrome P450 enzyme
-P450 enzyme consists of more than 30 types
-enzymes may be induced or inhibited
-some metabolites produced can be toxic
-not all drugs undergo this phase
-process is usually followed by Phase II
explain Phase II reaction
-glucuronidation, acetylation, and sulfation reactions
-phase II reactions convert a parent drug to more polar (water soluble) inactive metabolites by conjugation of subgroups to -OH, -SH, -NH2 functional groups on drug
-Glutathione conjugation is most important defence as produces non-toxic metabolites that’s excreted in bile or urine
What are characteristics of DILI?
-asymptomatic elevation of liver enzymes
-acute/chronic liver disease
-hepatocytes filled with fatty droplets
-liver enlargement
-hepatitis
-cirrhosis
-liver failure/tumours
Assessment of DILI
-Drug exposure history dose, route
-latency period between exposure and onset
-use of any concomitant drugs
-LFTs
-rule out other cause
-liver biopsy
which toxic metabolite paracetamol linked to?
-N-acetyl-p-benzoquinone-imine (NAPQI)
How is paracetamol metabolised - which pathway?
–95% metabolised by glucuronidation and sulphate pathway - produces non-toxic metabolite
–5% metabolised by P450 enzyme so can produce toxic metabolite NAPQI
-usually there is enough glutathione to detoxify metabolite
what happens in paracetamol overdose?
-more NAPQI is produced
-the glutathione stores are depleted faster
-so NAPQI accumulates leads to hepatic necrosis
-Also there will be raised transaminases
What is treatment of paracetamol toxicity?
-Acetylcycteine is given
-contains sulfhydryl compound
-administered via IV route
-most effective given within 8 hours
How does Acetylcysteine work for paracetamol overdose?
-restores hepatic glutathione
-combines directly to toxic metabolite NAPQI
-also source of sulphate to prevent hepatic damage
what does glutathione do in paracetamol overdose?
-it detoxifies the toxic metabolite of paracetamol (NAPQI)
What can co-amoxiclav lead to?
-can cause cholestatic liver disease
-this is where bile formation or flow is impaired
-liver bile is a greenish-yellow fluid that contains waste products
-it carries waste and breaks down fat during digestion
co-amoxiclav toxicity properties
-liver toxicity is 6x more than with amoxicillin
-risk increases after 14 day of treatment
-can occur during or shortly after treatment
-self limiting- rarely fatal
-more common in MEN
-More common in patients age above 65
flucloxacillin toxicity
-rare cholestatic liver disease
-can occur up to 2 months after treatment has stopped
-risk increases more than 14 days after treatment
explain alcohol induced liver disease
-chronic alcohol ingestion causes progressive liver disease
-phase goes from fatty liver —alcoholic hepatitis (inflammation)—cirrhosis (scarring of liver)
-Fatty liver and alcoholic hepatitis is reversible with alcohol cessation
-Cirrhosis is irreversible
-cirrhosis can occur after more than 10 years of daily ingestion of 6-8 drinks a day
how does alcohol metabolism take place?
-Alcohol dehydrogenase enzyme is present in GI mucosa
-some alcohol is metabolised to acetaldehyde
-remaining alcohol is absorbed from GI tract
-alcohol enters body tissue easily due to its lipophilic nature
-metabolised in liver
-micromosal ethanol oxidising system also makes acetaldehyde
-acetaldehyde has direct toxic effects
-women metabolise less alcohol so more prone to cirrhosis
what can alcohol induced cirrhosis of liver lead to?
-Portal hypertension
-Ascites - when too much fluid builds up in abdomen
-hepatic encephalopathy - impaired brain function
-Oesophageal varices and variceal bleeding
what is normal portal pressure?
5-10mmHg
portal hypertension mechanism
-increased resistance to blood flow through portal vein
-portal vein occlusion is where there is blockage or narrowing of portal vein by blood clot
-Hepatic vein obstruction prevents blood from flowing out of the liver and back to the heart. This blockage can cause liver damage.
-this also activates renin-angiotensin-aldosterone system which increases aldosterone and sodium retention
How is portal hypertension treated
-Non-selective beta blocker
-e.g. Propranolol
How does non-selective beta blocker work e.g. propranolol?
-Lowers cardiac output
-by blocking beta2 receptors, producing splanchnic vasoconstriction and reducing portal flow
what dose of propranolol should be used in portal hypertension?
-start low and titrate
-half time is prolonged
-initial dose is 10mg twice to three times daily
what is varices and variceal bleeding?
-serious complication of portal hypertension
-blood flow to liver is delayed
-blood diverted back to systemic circulation
-formation of varices mainly in oesophagus but also in stomach and rectum
what is varices and variceal bleeding?
-serious complication of portal hypertension
-blood flow to liver is delayed
-blood diverted back to systemic circulation
-formation of varices mainly in oesophagus but also in stomach and rectum
what are signs and symptoms of varices?
-haematemesis (vomiting blood)
-pallor (paleness)
-fatigue
-weakness
-high mortality rate
how do you treat varices or variceal bleeding?
-Vasopressin (IV)
-Reduces blood flow into splanchnic circulation by vasoconstriction
-GTN as a patch or IV given to prevent ischemic side effects
-contraindicated in ischemic heart disease
what is the first line for varices/variceal bleeding?
-Terlipressin (IV)
- Analogue of vasopressin with longer half life
-fewer systemis side effect e.g. cramps
-GTN still recommended
-portal pressure reduced
which drug is given for the prevention of re-bleeding with varices?
-Propranolol
-lowers risk of re-bleeding by 40%
What is Ascites?
-accumulation of fluid in peritoneal cavity
-most cause is cirrhosis from alcoholism
-can be due to portal hypertension
-may be due to low serum oncotic (osmotic) pressure caused by hypo-albuminaemia
what is the role of albumin?
-protein that maintains oncotic pressure
-helps to prevent fluid from leaking out of blood vessel and into other tissues
what does low albumin levels lead to?
-increases leakage of fluid from vascular space into body tissues leading to ascites and varices
what are the treatment options for ascites?
- Advise alcohol abstinence
- Bed rest
- Dietary sodium and fluid restriction
- Drug treatment e.g. spironolactone
how is spironolactone used for ascites?
-First line!!!
-aldosterone antagonist
-blocks aldosterone receptors in distal convoluted tubule to reduce sodium and water retention
- Start with 100mg daily titrating to 400mg daily
-aim for weight loss of 0.5-1kg per day
what are the side effects of spironolactone?
-hyperkalaemia
-female breasts in men
feeling dizzy
-muscle cramps
which loop diuretic must be added if spironolactone is inefficient?
-Furosemide 20mg daily
how should you monitor patients with ascites?
-weight and urine output daily
-electrolyte concentration
-renal function
-avoid dehydration and hyponatraemia (low sodium levels)
what is hepatic encephalopathy
-neuro-psychiatric complication of cirrhosis
-decreased cognition
-confusion
-slurred speech
-tremor in hands (asterixis)
-sweet smell on breath (hepatic fetor)
how is hepatic encephalopathy caused?
accumulation of toxic substances e.g. ammonia
-increased GABA levels and benzodiazepines
-increased levels of aromatic aminoacids
what increases risk of hepatic encephalopathy?
-infection
-excess protein from diet
-fluid depletion
-constipation
-electrolyte imbalance
-antidepressants
how is hepatic encephalopathy treated?
Remove or correct precipitating factors
Advise low protein diet
Drug treatment
which drug can be used for hepatic encephalopathy?
LACTULOSE
-non-absorbable disaccharide
-30ml four times a day
-decreases GI transit time and decreases ammonia production in the gut
-its broken down by GI bacteria
-avoid causing excessive diarrhoea
how is NEOMYCIN used in hepatic encephalopathy?
-reduces plasma ammonia levels
-decreases protein metabolising bacteria in GI tract
-dose: 1gram Four times a day for 5-7 days
what are the side effects of neomycin?
-ototoxicity (hearing problems)
-nephrotoxicity
what is the latency period between exposure and injury for DILI?
5-90 days
after how many weeks is there improvement in LFTs?
2-4 weeks after drug discontinuation
when should acetylcysteine be given after paracetamol overdose?
best if given within 8 hours
