Drug metabolism and liver disease 211

Drug metabolism and liver disease

• The vast majority of drugs, including anaesthetic drugs, are metabolised
by the liver (Table 8.5).
• Most drugs are initially metabolised by the cytochrome P450 system.
In phase I, they are either oxidised or reduced, and in phase II, they are
conjugated with a glucuronide, glycine or sulphate to enhance water
solubility and excretion in bile or urine.
• In early alcoholic liver disease, the cytochrome P450 system is often
induced, leading to rapid metabolism of drugs, whereas this is reversed
in end-​stage disease.
• The liver has a large functional reserve, so these functions are usually
preserved until end-​stage disease.
• Pharmacodynamics and the sensitivity of target organs for sedatives and
anaesthetics may be altered, with coma easily induced in end-​stage liver
disease.
• d portal blood flow in hepatic fibrosis reduces 1st-​pass metabolism.
• Hypoalbuminaemia increases free drug in plasma.
• There is an i volume of distribution due to ascites and Na+/​water
retention.
• Biotransformation enzymes may increase or decrease activity.
• Reduced liver cell mass results in reduced enzyme synthesis (e.g. plasma
cholinesterase) activation or deactivation.
• d biliary excretion of drugs due to obstructive jaundice.

Table 8.5  Anaesthetic drugs in liver failure

Drugs safe in liver Drugs to be used with Drugs

failure caution (may need contraindicated in
reduced dosage) liver failure
Premedication Lorazepam Midazolam, diazepam

Induction Propofol,
thiopental,
etomidate
Maintenance Desflurane, Enflurane Halothane
sevoflurane, (possibly)*
isoflurane, N2O
Muscle Atracurium, Rocuronium,
relaxants cisatracurium vecuronium,
suxamethonium
Opioids Remifentanil Fentanyl, alfentanil,
morphine, pethidine
Analgesics Paracetamol NSAIDs, lidocaine,
bupivacaine
*
Halothane has been rarely reported to cause hepatitis (see % p. 213).
21

212 Chapter 8 Hepatic disease

Postoperative liver dysfunction or

jaundice
Postoperative jaundice is relatively common; haematoma reabsorption or
blood transfusion can result in a high bilirubin load. Significant liver dysfunc-
tion is uncommon in previously healthy patients.
Mild elevation of liver transaminases has a varied aetiology and often re-
solves without treatment. LFTs more than double the normal range suggest
hepatocellular injury. Hepatitis due to volatile agents is extremely rare, es-
pecially with newer agents, and is largely a diagnosis of exclusion.
• Common causes include reduced hepatic O2 delivery 2° to hypoxia or
hypotension, drugs, trauma or infective causes (Table 8.6).
• Benign postoperative intrahepatic cholestasis mimics biliary obstruction
and usually occurs after major abdominal surgery.

Table 8.6  Causes of postoperative liver dysfunction or jaundice

Bilirubin overload Blood transfusion

(haemolysis) Haematoma resorption
Haemolytic anaemia (sickle-​cell, prosthetic heart valve,
glucose-​6-​phosphate dehydrogenase deficiency)
Hepatocellular injury Exacerbation of pre-​existing liver disease
Hepatic ischaemia: hypovolaemia, hypotension, cardiac
failure
Septicaemia
Drug-​induced (antibiotics, halothane)
Hypoxia
Viral hepatitis
Cholestasis Intrahepatic (benign, infection, drug-​induced, e.g.
cephalosporins, carbamazepine, erythromycin)
Extrahepatic (pancreatitis, gallstones, bile duct injury)
Congenital Gilbert’s syndrome

Halothane hepatitis
The use of halothane has been largely superseded by other volatile agents,
so it is becoming a historical phenomenon. Halothane has been linked to
postoperative liver dysfunction. Two syndromes are recognised:
• The first is associated with a transient rise in LFTs and low morbidity,
often after initial exposure.
• The second is thought to occur after repeated exposure and has an
‘immune’ mechanism with the development of fulminant hepatic
failure and high mortality. It is rare, with an incidence of 1 in 35 000
anaesthetics.
• Antibodies specific to fulminant hepatic failure patients exposed to
halothane are found in 70% of such patients. It is postulated that a
halothane oxidative metabolite binds to liver cytochromes to form a
hapten and induces a hypersensitivity reaction. All patients exposed to
halothane have altered liver proteins, but it is unknown why only a few
develop liver failure.