Hepatology - Drugs and the liver

Question 1

Are LFTs a reliable measure of hepatic function?

Answer 1

No. There is no single test that can evaluate liver function. Physical exam can reveal signs of chronic liver disease (e.g. jaundice, hepatomegaly, clubbing, spider naevi, ascites etc). USS can provide further details and assess for cancer. LFTs are incorrectly named, as they do not provide a measure of liver synthetic function. PT and Albumin are better measures.

Question 2

What is the Child Pugh score?

Answer 2

Assesses one and five year survival in patients with chronic liver disease using 5 variables: bilirubin, albumin, INR, ascites, and hepatic encephalopathy. It stages patients as Child class A, B or C which can give an indication about the patients ability to metabolise certain drugs.

Question 3

What drugs are commonly associated with liver injury?

Answer 3

Paracetamol - causes dose dependent acute liver injury
Co-amoxiclav and flucloxacillin - cause cholestatic hepatitis that resolves in most cases after drug withdrawel
NSAIDs - cholestatic hepatitis
Anti-TB drugs
Methotrexate - causes severe fibrosis and cirrhosis
Amiodarone - causes steato hepatitis
Chlorpromazine - cholestatic hepatitis
Anabolic steroids - cholestatic hepatitis

It is important to take a drug history over the last 6 months. Statins most commonly cause a mild transaminitis (a rise in ALT or AST). Elevations occur in approximately 2%. Despite this you can safely prescribe statins to a patient with mild liver dysfunction.

Question 4

How does paracetamol cause toxicity?

Answer 4

Paracetamol is metabolised by the liver and metabolism is required for paracetamol toxicity. Liver injury does not occur until glutathione has been depleted. After this, the reactive metabolites of paracetamol bind to cellular macromolecules, causing necrosis of hepatocytes. The antidote to paracetamol poisoning is acetylcysteine, which augments glutathione levels. 10g of paracetamol is sufficient to cause liver damage.

Question 5

When should patients be treated for paracetamol toxicity?

Answer 5

Patients whose paracetamol concentrations are on or above the treatment curve should be treated with NAC by iv. infusion (or if NAC cannot be used, with methionine by mouth provided the overdose has been taken within 10-12 hours and the patient is not vomiting). Also, patients presenting after 8 hours who have taken potentially toxic amounts should commence NAC even if plasma concentrations are not available. Treatment is determined on whether the paracetamol concentration is above the treatment line or not.

Question 6

What are the 2 main processes of drug metabolism in the liver?

Answer 6

Phase 1 - drug is made more polar by oxidation, reduction or methylation so it can combine with another molecule. The cytochrome P450 complex is responsible for the majority of phase 1 reactions. In cirrhosis, the activity of these enzymes can be significantly reduced.

Phase 2 - conjugation, which results in water soluble compounds that is usually inactive and more easily excreted in the urine or bile. Some of the phase 2 reactions have been shown to be impaired in liver disease.

Both of these phases can be affected by liver dysfunction necessitating dose reductions of some drugs.

Question 7

What commonly prescribed drugs require dose adjustment in liver dysfunction?

Answer 7

Fluoxetine - extensively metabolised by cytochrome enzymes and excreted renally.

Nifedipine - elimination half life is prolonged in liver dysfunction and the total clearance reduced. Dosage reduction may be needed in liver dysfunction.

Phenytoin - extensively metabolised in the liver so reduced dose may be required in liver function. Also bound to plasma proteins, which may be reduced in liver impairment resulting in a decreased total phenytoin plasma concentration. However, a free drug (active) concentration is unlikely to be altered.

Question 8

What is first pass metabolism? How is this affected in liver disease?

Answer 8

Many drugs taken orally will be subject to first pass metabolism. They will pass through the liver and be partially or wholly metabolised 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 longer. However, patients with cirrhosis often develop collaterals enabling the blood to bypass the liver resulting in a DECREASE in first pass metabolism.

In patients who have developed these shunts drugs which are usually subject to extensive first pass metabolism will have a higher plasma concentration than usual. These drugs would normally have a low oral bioavailability but in advanced liver disease this can increase up to 100%. In such doses you would need to prescribe lower doses.

Question 9

How can liver enzyme inducers or inhibitors affect the metabolism of some drugs?

Answer 9

The degree of drug metabolism in the liver can be affected by the induction or inhibition of cytochrome P450 liver enzymes. The P450 system is a family of isoenzymes, responsible for most phase 1 reactions. The most significant in terms of drug interactions is P450 3A4.

Enzyme inducers:

• metabolism would increase for drugs that are a substrate for enzymes leading to lower plasma concentrations
• reduced plasma concentration –> reduced therapeutic effect
• e.g. co prescribing carbimazole and COC

Enzyme inhibitors:

• concentration of affected drug would be expected to rise
• increased plasma concentration —> toxicity
• e.g. co prescribing erythromycin and tacrolimus leads to increased serum tacrolimus concentrations and tacrolimus toxicity (AKI)

Question 10

What drugs can have an effect on plasma ciclosporin concentrations?

Answer 10

1) Rifampicin - induces CYP 3A4 leading to decrease in plasma ciclosporin concentrations which could lead to transplant rejection
2) Grapefruit juice - inhibits CYP 3A4 which may significantly increase the plasma ciclosporin concentration
3) Fluconazole - inhibits CYP 3A4 which increases plasma ciclosporin concentrations. This is a dose dependent effect, so low doses of Fluconazole may not affect plasma ciclosporin concentrations

Question 11

What drugs can exacerbate encephalopathy in liver disease?

Answer 11

Drugs that cause:
Sedation (e.g. BDZ)
Agitation (e.g. antipsychotics)
Constipation (e.g. opioid analgesics)
Electrolyte disturbances (e.g. diuretics)

All have the potential to exacerbate encephalopathy associated with liver disease.

Question 12

What drugs can exacerbate clotting factors in liver disease?

Answer 12

Drugs that cause:
Thrombocytopaenia (e.g. sodium valproate)
Increased risk of bleeding (e.g. anti-coagulants, antiplatelets)

Question 13

What drugs have the potential to exacerbate ascites in liver disease?

Answer 13

Drugs that cause:
Fluid retention (e.g. NSAIDs)
Increase body sodium (e.g. sodium chloride infusion)

Question 14

What drugs can exacerbate gastric and oesophageal varices?

Answer 14

Drugs that cause:
Irritation to the GIT (e.g. NSAIDs)
Increase risk of bleeding (e.g. anticoagulants)

Question 15

What general considerations are important when prescribing in liver disease?

Answer 15

Identify at risk patients
Monitor LFTs, bilirubin, albumin and pro thrombin time at baseline and at regular intervals throughout treatment
Monitor drug concentrations to avoid toxicity
Drugs dependent on liver metabolism are likely to need dose reduction

Question 16

What class of anti-hypertensive is contraindicated in severe liver disease (Child’s C)?

Answer 16

ACEi.
In severe liver disease, the patient relies in part on activation of the renin angiotensin aldosterone system to maintain vascular resistance. Administration can lead to a rapid drop in blood pressure and cause renal failure. They can also cause hyperkalaemia.