Hepatic Dysfunction Flashcards
What drugs are contradicted in severe liver disease
- NSAIDS - can cause an ideosyncratic hepatitis
- paracetamol - dose dependent acute liver injury
- co-amoxiclav and flucloxacillin can cause cholestatic hepatitis that resolves in most cases after withdrawal of the drug
- antituberculosis drugs - these can cause liver injury
- methotrexate - can cause severe fibrosis and cirrhosis if not adequately monitored
- amiodarone - can cause a steato-hepatitis
- ACE
What are NSAIDS contradicted in severe liver disease
- can worsen liver function and some renal function
- in severe liver disease renal blood flow is reliant on prostacyclins in the kidney and reducing renal blood flow and can lead to deterioration in renal function
Why would you not give spironolactone to renal failure patients
- spironolactone and can cause hyperkalaemia and renal dysfunction
Why is ACE contraindicated in severe liver disease (Child pugh score B and C)
- patient relies in part on activation of the renin angiotensin system to maintain peripheral vascular resistance
- administration of an ACE inhibitor can lead to a rapid drop in blood pressure and development of renal failure
- ACE can also cause hyperkalaemia effecting renal function
In alcoholic liver disease what is thiamine crucial in preventing
- It is crucial in preventing wernicke’s encephalopathy and korsakoff psychosis
What are the physical examination signs of hepatic function
- Spider naevi
- clubbing
- jaundice
- loss of secondary sexual hair
- gynaecomastia
- ascites
- splenomegaly
- peripheral oedema
what can an ultrasound scan provide in liver disease
- cirrhotic liver with splenomegaly
- ascities
What blood tests provide clues to liver function
- albumin
- prothrombin
- bilirubin
What is the child pugh score used for
- evaluate operative risk in patients with liver cirrhosis
What 5 things are considered in the child pugh score
- Biliruin
- serum albumin
- clotting time
- ascites
- encephalopathy
- each is scored out of 3 points
What are the classes of the child pugh score
- Class A - 5-6 points
- Class B - 7-9 points
- Class C - 10-15 points
- C is the most severe
What is the MELD score used for
- it is also used to assess liver function and used to rank patients waiting a liver transplant
What is the use of child pugh score
- can be a useful indicator of an individuals ability to metabolise a given drug
- evaluate operative risk in patients with liver cirrhosis
What information do you ask about in a drug history
- Do you take any medication from the doctors
- how long have you been taking them for
- do you take anything else at all
- what for
- how long for
- 6 month drug history
- recreational drugs
- boderline substances
- injections, topical agents, inhalers, ear/eye drops
How likely is aspirin in causing hepatic dysfunction
- positive correlation with aspirin and hepatitis
- hepatitis occurs with aspirin in a dose related manner
What type of liver injury does paracetamol cause
- typically causes a dose dependent acute liver injury rather than cholestasis
Does flucloxacillin cause liver injury
- hepatitis and cholestatic jaundice have been reported with flucloxacillin
- the reaction is idiosyncratic and not dose related
- onset may be delayed for up to two months post-treatment and the course of the reaction may last for some months
- change in liver function tests may occur but are reversible when the treatment is discontinued
What can statins cause to happen
- can cause a mild transaminitis - raise in ALT ro ast
- elevations in these enzymes occur in 2% of individuals taking statins
What can statins cause to happen
- can cause a mild transaminitis - raise in ALT ro ast
- elevations in these enzymes occur in 2% of individuals taking statins
- can still safely prescribe statins in patients with mild liver dysfunction
What is the leading cause of acute liver failure in the UK
150 mg/kg of acutely ingested paracetamol in less than one hour can lead to liver damage in adults
What are risk factors of hepatotoxicity
- chronic alcohol consumption
- co-medications
- poor nutritional intake
What is the antitdote to paracetamol poisoning
- Acetylcysteine
- this augments glutathione levels
Describe how liver damage occurs via paracetamol overdose
- paracetamol is metabolised in the liver and metabolism of paracetamol is required prior to hepatotoxicity
- liver injury does not occur until glutathione is depleted
- after this the reactive metabolites of paracetamol bind to cellular macromolecules causing lethal damage to the hepatocyte
patients whose plasma paracetamol concentrates are above the treatment line should be treated with …
Acetylcystiene by IV infusion
- paracetamol concentration on or above the treatment line should be regarded as carrying a serious risk of liver damage
when should treatment be commenced
- Treatment should be commenced if a patient has taken more than 150 mg/kg in any 24 hour period unless
- the plasma paracetamol concentration is undetectable
- the patient is asymptomatic
- LFTs, serum creatinine and INR are all normal
How does metabolism of drugs occur
- Phase 1
- phase 2
Describe the phases of drug metabolism
Phase 1
- renders the drug more polar by oxidation, reduction, or methylation so it can combine with another molecule
- the cytochrome P450 group of enzymes is responsible for the majority of phase 1 reactions
- in cirrhosis the activity of these enzymes can be markedly reduced
Phase 2
- conjugation
- this reslts in a water soluble compound that is usually inactive and more easily excreted in the urine or bile
- some mechanisms of phase 2 reactions such as glucuronidation and sulphation have been shown to be impaired in liver disease
what happens to drug metabolism if there is liver dysfunction
- there is a reduction in metabolism
- reduced metabolism will require dose adjustment for some drugs
Name drug doses that need adjusting after hepatic impairment
- fluoxetine
- nifedipine
- phenytoin
does first pass metabolism reduce oral bioavailability
- First pass metabolism will pass through the liver and be partially or wholly metabolized before reaching the systemic circulation reducing oral bioavailability
If blood flow through the liver is slowed a drug may be…
Subject to increased metabolism as it may stay in the liver for longer
What happens in cirrhosis that results in decrease first pass metabolism
- patients with cirrhosis develops collaterals enabling the blood to bypass the liver
- this results in a decrease in first pass metabolism
- this increases bioavaliability in the liver and the bioavaliability can increase to 100% as first pass metabolism is bypassed
- therefore you would reduced drug doses to avoid toxicity
what enzymes are important in first pass metabolism in the liver
- Cytochrome P450 in the liver or wall of the gut
What drug is the most significant in the P450 system
P450 3A4
- interactions can occur by induction or inhibition of other isoenzymes
what happens if P450 enzymes are induced
- extent of metabolism would increase for drugs that are a substance of the enzyme leading to lower plasma concentrations
- a decrease in plasma concentration may reduce therapeutic effect
- e.g. carbamazepine induces drug metabolising enzymes, co-administration of carbamazepine and the oral contraceptive pill leads to a decrease in both the oestrogen and progestogen concentration which reduces contraceptive cover
describe what happens if P450 enzymes are inhibited
- plasma concentration of the affected drug would be expected to rise
- an increase in plasma concentrations may lead to toxicity
- e.g. erythromycin is a potent inhibitor of P450 3A4, co-administration of erythromycin and tacrolimus has been shown to increase plasma tacrolimus concentration by up to 6 fold and can lead to tacrolimus toxicity causing acute renal failure
How does rifampicin affect CYP3A4
- induces CYP3A4
- this results in a decrease in plasma concentration of drugs
- therefore you need to increase the drug dose
What does grapfruit juice do to liver enzymes
- inhibits CYP3A4 - this can increase plasma concentration
when treating someone with encephalopathy what do you have to be careful when prescribing
Have to be careful when prescribing drugs that have the potential to
- cause sedation - (benzodiazepines)
- cause agitation (antipsychotics)
- cause constipation (opioid analgesics)
- cause electrolyte disturbances such as diuretics (diuretics)
In liver disease synthesis of clotting factors is reduced so what do you need to consider when prescribing drugs
Need to be careful when prescribing drugs that:
- cause thrombocytopenia (sodium valproate)
- increase the risk of bleeding ( anticoagulants, antiplatelets)
In liver disease where there is gastric and oesophageal varices what do you need to be careful when prescribing
Need to be careful when prescribing drugs that have the potential to:
- cause irritation to the gastrointestinal tract (NSAIDs)
- increase the risk of bleeding (Anticoagulants)
In liver disease where there is ascites what do you need to be careful of when prescribing
Need to be careful when prescribing drugs that have the potential to:
- cause fluid retention such as NSAIDS
- increase body sodium (such as sodium chloride infusion)
What do you have to be careful of when prescribing tramadol in liver disease
- Can cause constipation so encephalopathy
What general considerations should you consider hepatic dysfunction
- identify at risk patients
- monitor LFTs, albumin, pro thrombin time and bilirubin at baseline and at regular intervals throughout treatment with drug treatments known to cause hepatotoxicity
- monitor drug concentration where possible to avoid toxicity which can cause liver injury
- avoid drug interactions which may increase the risk of liver injury
- drugs that are dependent on the liver for metabolism are likely needed to have dose reduction
- drugs that increase risk of bleeding should be avoided
What does bioavailability give an indication of
- Gives an indication of the extent of first pass metabolism
What can decrease first pass metabolism
- liver dysfunction if portosystemic shunts are present
Half life can be…
extended in patients with liver dysfunction
How is protein binding effected in liver disease
- decreased serum albumin may lead to a decrease in total drug concentration for those drugs which are highly protein bound
- but the concentration of free drug is generally unchanged
What characteristics drugs are important when prescribing in hepatic dysfunction
- bioavailability
- metabolism
- half-life
- extent of protein binding
- excretion
- adverse effects
- hepatotoxicity
- nephrotoxicity
What do you do if you suspect a drug is the cause of liver injury
- stop the suspected medicine
- give treatment where necessary
- monitor liver function
- if the reaction is serious or the reaction has occurred with a new drug or new indication report this to the yellow card scheme
