Drugs in liver disease Flashcards
What do we measure when performing LFTs?
Alanine aminotransferase
Aspartate aminotransferase
Alkaline phosphatase
Gamma glutamyl transferase
Liver enzymes
Bilirubin
Albumin
INR (indicator of a clotting agent)
Prothrombin time (time it takes body to clot)
Why is aminotransferases used in LFTs?
ALT + AST
Used to detect damage to hepatocytes + liver injury
ALT is more specific than AST
Very high levels of ALT in acute injury (binge night)
Levels can be elevated due to drugs, infective agent or substances that are toxic to the liver
Levels are usually not high in chronic hepatitis
Causes of elevated levels:
- obstruction of bile ducts
- cirrhosis (resulting from chronic hepatitis)
- tumors in the liver
Why is alkaline phoshatase used in LFTs?
Detects cholestasis
If the flow of bile is obstructed, the blood levels of ALP is high
ALP is present in bone cells too (so non-specific)
Liver-derived ALP located outside of bile membrane reflecting bile duct obstruction
If ALP results increase, but it is not clear if its due to liver/bone disease, we use this test against other LFT results.
Why is gamma glutamyl transferase used in LFTs?
GGT enzyme is released in all types of liver dysfunction so cannot be used to differentiate
Raised GGT with raised ALP/bilirubin can suggest cholestatic damage
Raised GGT in isolation can occur in alcohol abuse/enzyme inducing drugs (hepatic damage)
How can you differentiate between hepatic + cholestatic damage?
Why is bilirubin used in LFTs?
Produced by the destruction of RBCs
Non-specific as its also released in haemolytic anaemias
Hepatocytes transform unconjugated bilirubin into a water-soluble conjugated form which is excreted via bile into the intestine
Jaundice = >50micromol/L serum bilirubin levels
Cholestatic cause alongside ALP + GGT
Seen in hepatic damage where there is decreased metabolism of unconjugated bilirubin to conjugated bilirubin
Jaundice can hep determine if cause is either conjugated/unconjugated hyperbilirubinaemia
Why is albumin used in LFTs?
Liver is responsible for manufacture of plasma proteins
Albumin is a marker of synthetic function of the liver
Non-specific as it is low in malnourished pts, nephrotic syndrome
Albumin has a half life of 20 days = indicates chronic liver disease (for time) than acute
What is a clotting screening blood test?
Includes prothrombin time (PT) + INR (international normalised ratio = ratio of patient’s prothrombin time compared to control)
Liver is responsible for production of vitamin K-dependent clotting factors
If INR increases, this indicates synthetic function of the liver has decreased/absorption of vitamin K is impaired
Non-specific as abnormal in pts on vit. K antagonist or have coagulopathy disorders
Changes in PT occur more rapidly than changes in albumin (helpful in predicting hepatocellular damage in acute situations)
What are the types of liver disease?
Acute/chronic (>6 months)
Cirrhosis
healthy liver > fatty liver > alcoholic hepatitis > cirrhosis
Cholestasis (reduction/stoppage of bile flow)
Compensated + decompensated
What is the use of a child-pugh score?
Tool used to assess the severity of chronic liver disease, but no indicator of metabolic capacity
Each 5 parameters is given a score (ascites, encephalopathy, nutritional status, albumin + bilirubin)
Total score is converted to a grade A, B or C (C mean most advanced disease)
SPCs recommend that dosing is based on child-pugh score
What are the drugs that induce liver disease?
Amiodarone
Azathioprine
Carbamazepine
Isoniazid
Methotrexate
NSAIDs
Antibiotics e.g. co-amoxiclav and flucloxacillin
Paracetamol
Phenytoin
Rifampicin
Sodium valproate
Statins
Which is the most important for hepatic metabolism?
Lipid-soluble drugs or water-soluble drugs?
Lipid-soluble
Water-soluble is readily renally excreted
Many medications undergo a two-stage metabolic process.
What are they?
Phase 1 = metabolism e.g. CYP450 enzymes
Phase 2 = biotransformation with conjugation of the drug or its metabolite (e.g. glucuronidation + sulphation)
CYP-mediated reactions affect liver disease more than phase 2
What are the absorption pharmokinetic changes in liver disease?
Decrease gut motility in cirrhosis = delay in gastric emptying + reduction in the rate
Reduced absorption + bioavailability of lipophilic drugs occur in cholestasis
Drugs have low bioavailability due to high FPM, therefore dose reducing due to increased FPM
What are the distribution pharmokinetic changes in liver disease?
Prescence of ascites (accumulation of fluid) increases volume of distribution for water-soluble drugs (e.g. gentamicin) leading to decreased drug concentration
Low albumin may affect drugs which are highly protein bound (leads to higher conc. of free drug + potential toxicity)
Excess bilirubin can displace highly protein bound drugs from binding sites leading to free drug
