Prescribing in hepatic dysfunction

Question 1

What are the clinical examination findings associated with chronic liver disease? (8)

Answer 1

Spider naevi
Clubbing
Jaundice
Loss of secondary sexual hair
Gynaecomastia
Ascites
Splenomegaly
Peripheral oedema

Question 2

If someone with chronic liver failure was to undergo an ultrasound, what would the ultrasound show that would indicate liver failure?

Answer 2

cirrhotic liver with splenomegaly, and sometimes ascites.

Question 3

Liver function tests are incorrectly named as they do not provide you with information regarding the function of the liver. Which tests are able to provide this information?

Answer 3

Blood tests for-

• Albumin
• Prothrombin
• Bilirubin

Question 4

Which score is able to provide you with information on the risk of operating on someone with liver Cirrhosis? Describe the parameters of the score.

Answer 4

Child Pugh score - assesses
Serum Bilirubin severity 
1 Point = <34
2 points = 35-50
3 points = >50

Serum albumin (How low)
1 point = >35
2 points = 28-35
3 points = <28

INR (how high)
1 point = <1.7
2 points = 1.71- 2.20
3 points = >2.20

Ascites severity
1 point = None
2 points = moderate
3 points = moderate or sever

Hepatic encephalopathy
1 point = none
2 points = grade 1-3 (surpressed with medication)
3points = grade 3 to 4

Class A Mild 5-6
Class B Moderate 7-9
Class C Sever 10-15

Question 5

Which antibiotics is associated with hepatic and cholestatic jaundice? What would you do under these circumstances?

Answer 5

flucloxacillin and Co-amoxiclav
The onset may be delayed for up to two months post-treatment, and the course of the reaction may last for some months
Discontinue the drug

Question 6

When taking a drug history, how many months of a drug history should you ask for?

Answer 6

As about drugs taken in the last 6 months

Question 7

Which drugs are known to cause liver injury, there are many but list 6. Which of these drugs cause dose dependant damage? And which type of liver damage can they cause?

Answer 7

Paracetamol - dose dependant acute liver injury which cause cause liver failure

NSAIDS - ideosyncratic hepatitis that resolves in most cases after stopping drug (can cause hepatotoxicity or cholestatic hepatitis but this is rare. Ibuprofen can cause cholestatic hepatitis)

Aspirin - Dose dependant hepatitis

Antituberculosis drugs (rifampicin) - can cause liver injury

Methotrexate - can cause severe fibrosis and cirrhosis if not adequately monitored.

Amiodarone - can cause a steato hepatitis.

Co-amoxiclav and flucloxacillin - cholestatic hepatitis (hepatitis and cholestatic jaundice) that resolves in most cases after stopping drug

Question 8

When taking a drug history - list all the drugs you should ask about

Answer 8

• Medication
• Vitamines
• Herbal
• Eye/Ear drops
• Inhalers
• Injections
• Topical agents
• Recreational drugs
• Food and dietary supplements

Question 9

Can stains cause liver injury? Can it be prescribed in those with liver dysfunction?

Answer 9

Statins causes a mile increase in transaminase (AST AND ALT)

Can be prescribed in those with mild liver dysfunction (e.g non-alcoholic fatty liver disease patients) as long as you monitor the LFTs

Question 10

What is the amount of paracetamol that can lead to liver damage in adults?

Answer 10

150mg/kg of paracetamol in under 1h

Question 11

Where is paracetamol mainly metabolised?

Answer 11

In the liver

Question 12

In the case of liver injury caused by paracetamol, what has to be depleted before the paracetamol can cause liver damage?

Answer 12

glutathione
After this, the reactive metabolites of paracetamol bind to cellular macromolecules, causing lethal damage to the hepatocyte.

Question 13

What is the antidote to paracetamol poisoning and how does it work?

Answer 13

acetylcysteine, which augments glutathione levels.

Increase the synthesis of glutathione

Question 14

Treatment for paracetamol overdose should be commenced if a patient has taken more than 150 mg/kg in any 24-hour period, unless what>?

Answer 14

The plasma-paracetamol concentration is undetectable

The patient is asymptomatic

LFTs, serum creatinine and INR are all normal

Question 15

Which graph is used to assess if a patient should be give acetylcysteine to treat paracetamol overdose?

Answer 15

MHRA’s paracetamol overdose treatment graph

Question 16

If a patient has taken toxic amounts of paracetamol but you have no access to their plasma concentration levels, should they still be given acetylcysteine?

Answer 16

only for Patients presenting after 8 hours who have taken potentially toxic amounts of paracetamol - even if plasma concentrations are not available.

Question 17

Describe the 2 main phases of drug metabolism in the liver

Answer 17

Phase 1- makes drug more polar via 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. Enzyme activity reduced in cirrhosis

Phase 2- Conjugation which produces a water soluble compound which is usually inactive and more easily excreted in urine or bile. Some mechanisms of Phase 2 reactions, e.g. glucuronidation and sulphation, have been shown to be impaired in liver disease.

Question 18

Give examples of some drugs that would require dose adjustment if patient has sever liver failure

Answer 18

Fluoxetine (selective serotonin reuptake inhibitor - antidepressant)

Nifedipine (calcium channel blocker)

Phenytoin ( anticonvulsant used for tonic clonic, convulsive status epilepticus, partial seizures with or without generalisation )

Question 19

What is first pass metabolism?

Answer 19

A drug gets metabolized (partially or completely) at a specific location in the body that results in a reduced concentration of the active drug when it reaches its site of action or the systemic circulation. The first pass effect is often associated with the liver but it can also occur in the lungs, vasculature, GI tract,

Question 20

How does liver dysfunction and failure effect first pass metabolism? What are the implications of this?

Answer 20

Liver is a very common site for first pass metabolism.

If the blood flow through the liver is slowed, a drug may be metabolised faster, as it may stay in the liver for longer.

Patients with cirrhosis can develop collaterals. This enables blood to bypass the liver (shunts). This reduces first pass metabolism.

In patients with this condition, drugs which should have a reduced bioavailability due to first pass metabolism will have a higher plasma concentration than usual. Bioavailability may approach 100% as opposed to a fraction of this amount (10,15,2030%)

You may need to prescribe reduced doses to avoid toxicity

Question 21

What are the side effects of morphine and how can they effect someone with liver disease or failure?

Answer 21

Side effects- Constipation, confusion , drowsiness

Morphine causes liver failure. This increases the risk of hepatic encephalopathy in someone with liver failure, to counter act this, increase the dose of laxative e.g lactulose. This should already be prescribed to a patient at risk of hepatic encephalopathy

The confusion and sedation caused by morphine and other opioids like tramadol may also mask the signs of encephalopathy so must be careful

Question 22

Which isoenzymes are responsible for phase 1 reactions in the liver?

Answer 22

Cytochrome P450 enzymes

Most significant is the P450 3A4

Question 23

What can happens if Cytochrome P450 enzymes are induced? Give an example of a drug which can induce the enzyme and how it can effect other drugs.

Answer 23

Extent of metabolism would increase for drugs that are a substrate of the enzyme, leading to lower plasma concentrations.

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.

Question 24

What can happens if Cytochrome P450 enzymes are inhibited? Give an example of a drug which can inhibit the enzyme and how it can effect other drugs.

Answer 24

Plasma concentration of the affected drug would be expected to rise.

An increase in plasma concentrations may lead to toxicity

Erythromycin is a potent inhibitor of P450 3A4. Co-administration of erythromycin and tacrolimus (imunisuprrssant used for organ transplants and atypical for eczema) has been shown to increase plasma tacrolimus concentrations by up to 6-fold and can lead to tacrolimus toxicity, causing acute renal failure.

Question 25

List some drugs which can cause induction of Cytochrome P450 enzymes

Answer 25

carbamazepine

Rifampicin

Question 26

List some drugs which can cause inhibition of Cytochrome P450 enzymes

Answer 26

Erythromycin
Grapefruit juice
Fluconazole (antifungal used for candidiasis and meningitis)

Question 27

In liver disease Encephalopathy can develop, Which types of drugs should you take care when prescribing that can precipitate or exacerbate Encephalopathy

Answer 27

Cause sedation (e.g. benzodiazepines).

Cause agitation (e.g. antipsychotics).

Cause constipation (e.g. opioid analgesics).

Cause electrolyte disturbances (e.g. diuretics).

Question 28

People with liver disease can have clotting abnormalities due to a reduction in clotting factors. Which drugs should you be careful in prescribing with this in mind?

Answer 28

Cause thrombocytopenia - low platelets (e.g. sodium valproate).

Increase the risk of bleeding (e.g. anticoagulants, antiplatelets).

Question 29

People with liver disease can have develop gastric and oesophageal varices. Which drugs should you be careful in prescribing with this in mind?

Answer 29

Cause irritation to the gastrointestinal (GI) tract (e.g. NSAIDs).

Increase the risk of bleeding (e.g. anticoagulants).

Question 30

Which drugs can precipitate ascites in those with liver failure?

Answer 30

Cause fluid retention (e.g. NSAIDs).

Increase body sodium (e.g. sodium chloride infusion).

Question 31

Which pain medication is contraindicated in liver disease and why?

Answer 31

NSAIDS

Diclofenac is contraindicated. The risk of bleeding is increased. NSAIDs can irritate the gastrointestinal tract, which may increase the risk of bleeding from GI varices. NSAIDs may also increase fluid retention in ascites. Patients with liver failure may depend on renal prostaglandins to maintain blood flow. NSAIDs inhibit prostaglandin production, reducing renal perfusion and can therefore precipitate renal impairment.

Question 32

When treating patients with liver failure, with drugs you know to be hepatotoxic, what should you make sure to monitor?

Answer 32

LFTs, albumin, pro thrombin time and bilirubin at baseline and at regular intervals throughout treatment

Question 33

Which drug characteristics should you consider when prescribing a drug for someone with liver failure?

Answer 33

Bioavailability -First-pass metabolism may be decreased in patients with liver dysfunction if portosystemic shunts are present.

Metabolism - Drugs mainly metabolised in the liver should be prescribed with caution

Half life- The half-life of a drug can be extended in patients with liver dysfunction.

Extent of protein binding- Decreased serum albumin may lead to a decrease in total drug concentration for those drugs which are highly protein bound. However, the concentration of free (i.e. pharmacologically active) drug is generally unchanged. Take care when interpreting the total plasma-concentration of these drugs.

Excretion- Does the drug undergo biliary excretion or enterohepatic circulation?

If biliary excreted (e.g. ethinylestradiol), excretion may be reduced in some biliary conditions.

Adverse effects- The adverse-effects of drugs can exacerbate the effects of liver dysfunction

Hepatotoxicity- Avoid hepatotoxic drugs where possible. This will reduce the risk of further liver injury.

Nephrotoxicity - Avoid nephrotoxic drugs where possible. Patients with chronic liver disease are at greater risk of renal dysfunction.