Prescribing in Hepatology Flashcards
What are the functions of the liver
- immunological
- metabolic homeostasis
- storage
- bile production
- biosynthesis such as albumin and clotting factors
- metabolisms e.g. drugs, toxic products such as ammonia
what are the two main phases of drug metabolism in the liver
- Phase 1 - metabolism by the cytochrome P450 enzyme family
- Phase 2 - conjugation
describe what happens in the phases of drug metabolism
Phase 1 - metabolism by the cytochrome P450 enzyme family
- activates the drug/metabolites (prodrug)
- reduces the bioavailability of the drug/metabolites (first pass metabolism)
- deactivates the drug/metabolites
Phase 2 - conjugation
- normally makes the metabolite water soluble so that it can be excreted
What are the symptoms of alcohol withdrawal syndrome
- anxiety
- nausea
- vomiting
- confusion
- anorexia
What chart is used to monitor symptoms and severity of alcohol withdrawal syndrome
- CIWA-AR chart
- take the score and is used to determine the treatment that patients require
what happens if a patient is scoring greater than 10 on the CIWA-AR chart
- given a benzodiazepine to help control the symptoms
What is the first line treatment for alcohol withdrawal
- chlordiazepoxide is first line treatment
- lorazepam is used in patients with liver cirrhosis
What enzyme metabolise benzodiazepines
- metabolised in the liver via CYP450
How do bezodiazepines work
- produce a sedative effect through enhancing gama-aminobutyric acid (GABA) - an inhibitory neurotransmitter
What are the common side effects of bezodiazepines
- confusion
- drowsiness
- respiratory depression
- hallucinations
- paradoxical effects
- agitation
- high risk of addiction with long term use
- associated with suicide ideation
- falls and fractures int he elderly
what is the 1st line choice on benzodiazepine that is used
Chlordiazepoxide - long acting
What is the half life of chlordiazepoxide
- half life of 6-30 hours with active metabolites
- accumulation half lives of 10-18 hours and 21-78 hours
Describe how the drugs are managed in the first 24 hours and on day 2 of alcohol withdrawal
chlordiazepoxide First 24 hours - prescribed on PRN section of chart - 25-50mg - 2 hourly as per CIWA- AR - maximum dose in 24 hours - 250mg - R/V if greater doses required
Day 2
- total dosing in first 24 hours is used to set detox regimen
- after first 24 hours stop the chlordiazepoxide prescribed on a PRN basis
- calculate the total benzodiazepines administered during the first 24 hours, prescribe in 4 divided doses and reduce by approx 20% or 10mg QDS daily
Why do you give lorazepam instead of chlordiazepoxide when the person has cirrhosis
- liver function is impaired therefore you don’t want to give chlordiazepoxide as it has a long half life and therefore can accumulate and might cause respiratory depression
- lorazepam has a short half life of 12 hours therefore there is a minimal risk of excessive accumulation
How do you prescribe lorazepam on the chart
- Prescribed on PRN section of chart. 1-2 mg, 2 hourly, As per CIWA-Ar,
- If doses greater than 10 mg/24 hrs – R/V patient
How much chlordiazepoxide equals 1mg of lorazepam
• Chlordiazepoxide 25mg (approximately) = Diazepam 10mg = Lorazepam 1mg
What is a severe form of alcohol withdrawal
- delirium tremens
What can high doses of benzodiazepines cause
- respiratory depression therefore transfer to the ITU
How do you treat seizures in alcohol withdrawal
- Lorazepam 2-4mg slow IV up to a maximum dose of 8mg in 24 hours
How do you treat psychotic symptoms of alcohol withdrawal
- Haloperidol 0.5-1.5mg IM or 1-2mg
- PO 2-3 times daily (only in combination with chlordiazepoxide)
what is also prescribed for alcohol withdrawal
Pabrinex
What is pabrinex
- this is a high strength mixture of vitamin B and C
What is the treatment dose of pabrinex
Treatment dose: 2 pairs IV pabrinex TDS for 3-5 days
Prophylactic dose: 1 pair TDS
What are the side effects of pabrinex
- risk of anaphylaxis/allergic reaction
Caution - glucose infusion before pabrinex/thiamine may deplete thiamine reserves and precipitate wernickes
What is pabrinex used to treat
Wernickes korakoff syndrome
What would you use after completing the pabrinex course
- Thiamine 100mg TDS PO
- A dietician review and nutritional supplements such as Fresubin may also be required
- vitamin B co-strong in those with poor nutritional intake and risk of refeeding
Who do you give vitamin B co-strong in
- poor nutritional intake
- risk of refeeding
what is encephalopathy
• Build up of toxins/ammonia in the body
What is the target of encephalopathy
2 soft stools a day
- need to eliminate ammonia through the gut
Name some symptoms of encephalopathy
- marked confusion
- stuporous
- neuromuscular disturbances
- asterxis
- hyperreflexia
- impaired thinking
What do you use to treat encephalopathy
- Lactulose
- phosphate enemas
- rifaximin - only in recurrent encephalopathy
How does lactulose treat encephalopathy
- Osmotic laxative
- local osmotic effect in the colon - there is increased faecal bulk and peristalsis
- high doses lead to a reduction in colonic pH, reducing absorption of and increasing excretion of ammonia
what is the downside of lactulose in treatment of encephalopathy
- can take up to 48-72 hours to work
- compliance issues - side effects include bloating, abdominal pain, nausea and taste
- dose varies from 15ml-50ml TDS dependent on patient
when are phosphate enemas given for treatment of encephalopathy
Given alongside lactulose as a STAT if patient is encephalopathic
What does phosphate enemas function as
- functions as a fast acting osmotic laxative
What does rifaximin do
Antibiotic - inhibits bacterial DNA dependent RNA polymerase
How is rifaximin used in encephalopathy
- gets rid of any gut bacteria
- poorly absorbed from the GI tract
- metabolised by the liver
- dose is 550mg BD
- prescribed only in recurrent encephalopathy
What are the side effects of rifaximin used in encephalopathy
- constipation
- abdominal pain
- ascities
- hyperkalaemia
- neutropenia
- depression
- dizziness
- withheld if patient is receiving systemic antibiotics
- interacts with ciclosporin
What drug does rifaximin interact with
interacts with ciclosporin
What is ascites
- Build up of fluid in the peritoneum
How do you treat ascites
- furosemide
- spironolactone
What do patients also benefit from when treating ascities
- Improvement in nutritional status
- Fluid / dietary sodium restriction
- Management of underlying liver disease
How does furosemide work when treating ascites
- Binds to the chloride site of the Na-K-2Cl co-transporter in the ascending Loop of Henle
- Inhibits sodium reabsorption, increasing diuresis
What dosage should furosemide be given in in ascites
• Started at 40 mg OM, increased up to 80 mg BD if
possible (second dose at lunchtime- so patient are not up all night going to the toilet )
What do you have to be cautious of when treating ascites using furosemide
- IV usage in ascitic patients due to the risk of AKI
What is the mechanism of action of spironolactone
Aldosterone antagonist
• Inhibits aldosterone-dependent Na-K exchange site in the distal convoluted renal tubule
What is the dosage of spironolactone used in ascites
- Normally started at 100 mg OM, increased to 400 mg if possible
- Much higher doses than those used in heart failure
What do you have to be careful of in spironolactone use in ascites
- can cause painful gynaecomastia
- consider switch to amiloride
- but this is less effective in cirrhosis patients so ideally want to keep them on spironolactone
What are the side effects of furosemide
- can reduce patients blood pressure
- can cause hypokalemia
- can cause hyponatremia
- AKI
What are the side effects of spironolactone
- can red patients blood pressure
- can cause hyperkaelima
- can cause hypernatremia
- AKI
furosemide and spironolactone are …
• Complementary when used in combination
what is the treatment for variceal bleed
- Initial treatment is in endoscopy
- patient is then started on a vasoconstrictor
- first line use at Barts is terlipressin
What is the half life of terlipressin
- long half life of 4-6 hours and a reduced effect on the kidneys and diuresis
how does terlipressin work
- acts on oesophageal varices by contraction of smooth oesophageal muscle causing compression of the varices
What are the side effects of terlipressin
- hypertension
- atherosclerosis
- cardiac dysrhthmias or coronary insufficiency
What can terlipressin do to blood pressure
- can cause an increase in blood pressure which can increase more in those with renal hypertension or blood vessel sclerosis
What do you need to monitor when using terlipressin
- ECG
- monitor blood pressure
- serum sodium, potassiuma and fluid balance
Describe the dosage of terlipressin
• Initially 2mg by intravenous bolus
• Then 1mg-2mg every four to six hours, until the bleeding
is controlled
• NICE and BSG recommend continuing treatment until haemostasis achieved or for up to 5 days
• Dose can be tapered down
what are beta blockers used for in varices
- they are prophylaxis
how do beta blockers work
Beta blockers are competitive antagonists that block the
adrenergic beta receptor sites
• Non-cardio selective beta-blockers preferred due to increased effect on portal pressures
What is the preferred beta blocker in varices
Carvedilol preferred due to complementary mild anti-alpha 1 adrenergic activity
what should you ask in the history if you think it is drug induced liver injury
Drug handling by the liver
• Is the drug metabolised by the liver?
• Is the drug toxic to the liver in overdose?
The type of hepatic injury
• Cholestatic
• Hepatitic
• Acute liver failure
Drug interactions
• Side effects, pharmacodynamics, pharmacogenetics
Any pre-existing liver disease or complications?
How much paracetamol can cause acute liver toxicity
Single 7.5 g dose can cause acute liver toxicity
How much paracetamol is needed to cause an ALP rise
• Three weeks of 4g/day (licensed dose) can cause ALP
(3xULN) rise in one third of patients
what markers rise in an overdose of paracetamol
- there is marked elevations in serum ALT and AST
what clinical symptoms can arise in an overdose of paracetamol
- Jaundice
- confusion
- hepatic failure
- potentially death
How does paracetamol lead to acute liver failure
- paracetamol is conjugated with glutathione, detoxified and secreted
- this forms N-acetyl-p-benzoquinoneimine
- this high dose leads to accumulation of the toxic metabolite
What are the risk factors of a paracetamol overdose
- increased metabolism of P450 system
- certain drugs
- chronic alcohol use
- decrease glutathione
- fasting
- malnutrition
- alcoholism
What is the treatment of a paracetamol overdose and how does it work
N-acetylcysteine (NAC) IV infusion
- mechanism not fully understood but;
• Restores glutathione levels or acts as an alternate substrate for conjugation
• Also antioxidant properties
How do you give NAC in paracetamol overdose
Highly effective in preventing liver damage if given within 8 hours of overdose. After this efficacy falls substantially; potential for severe hepatotoxicity
• FIRST INFUSION: Add 150mg/kg acetylcysteine to 200mL and infuse overone hour.
• SECOND INFUSION: Add 50mg/kg acetylcysteine to 500mL and administer over 4 hours.
• THIRD INFUSION: Add 100mg/kg acetylcysteine to 1000mL and administer over 16 hours.
- Continued treatment with acetylcysteine (given at the dose and rate as used in the third infusion) may be necessary depending on the clinical evaluation of the patient
what is the target for hepatitis B treatment
HBV DNA to go to undetectable levels and ALT to normalise.
what drugs do you use to suppress hepatitis B
- Tenofovir disoproxil
- entecavir
How does tenofovir work
Nucleotide monophosphate analogue;
• competitive inhibition, replaces the deoxyribonucleotide substrate in HBV DNA and acts as a chain terminator
• Eliminated through renal excretion
• Safe in pregnancy
What is the difference between tenofovir and entecavir
- Tenofovir is faster than entecavir at reducing viral DNA initially, but after 1 year has similar treatment effectiveness
- women of child bearing potential should not be started on entecavir
describe how entecavir works
- Competes with deoxyguanosine triphosphate, inhibiting reverse transcription of HBV DNA
- Eliminated through renal excretion
- Toxicity in pregnancy
What are the side effects for tenofovir and entecavir
- Long-term therapy may cause nephrotoxicity associated with lactic acidosis, Fanconi syndrome or a reduction in bone mineral density
- TDF believed to have higher nephrotoxicity in comparison to ETV
- Monitor creatinine and phosphate levels
How many genotypes does Hepatits C have
6 genotypes - with distinct subtypes within genotypes
What agents are available for hepatitis C
Multiple oral agents available; • Epclusa (sofosbuvir / velpatasvir) • Harvoni (sofosbuvir / ledipasvir) • Maviret (glecaprevir / pibrentasvir) • Zepatier (elbasvir / grazoprevir) • Vosevi (sofosbuvir / velpatasvir / voxilaprevir)
- may be used in combination with ribavirin
What is treatment of hepatitis C dependent on
Treatment based on genotype, presence of cirrhosis and previous treatment exposure as per NHS England guidance
Name 3 types of Hepatits C medications
- NS5A inhibitors
- NS5B inhibitors
- NS3/4A protease inhibitors
Give examples of hepatitis C medications
NS5A inhibitors • Velpatasvir • Pibrentasvir • Elbasvir • Ledipasvir
NS5B inhibitors
• Sofosbuvir
NS3/4A protease inhibitors
• Glecaprevir
• Grazoprevir
• Voxilaprevir
Patients with ascites secondary to liver cirrhosis should be given..
an aldosterone antagonists e.g. spironolactone
