1. Drugs and prescribing in Liver disease
Esther Unitt
Consultant Hepatologist

2. Objectives Paracetamol hepatotoxicity Management of alcohol withdrawal
Chronic liver disease
What pain relief can I give?
Diuretics
The confused liver patient
What do I do
Role of sedatives?

3. Paracetamol Overdose

4. Aetiology of Acute Liver Failure in UK and Europe. UK Europe
Paracetamol hepatotoxicity 54.1% 2%
Viral % 70%
HAV % 4%
HBV + HDV 9.0% 45%
Other % 3%
Indeterminate % 18%
Drug reaction 6.9% 14.5%
Miscellaneous 3.9% 12

5. Paracetamol as cause of acute liver failure
Commonest cause of ALF in UK (>50%)
Usually taken with suicidal intent
8% due to unintentional overdosing in ‘high risk’ patients
ALF occurs in 2-5% of patients who present following paracetamol OD
Median dose 40g (range 5-210g)

6. Paracetamol Nausea/vomiting (after 24hours) RUQ pain/tenderness
Liver damage maximal 3-4 days after ingestion
Encephalopathy, haemorrhage, hypoglycaemia, sepsis, cerebral oedema and death

7. N-acetylcysteine (Parvolex)
Treatment
N-acetylcysteine (Parvolex)

9. Metabolism of paracetamol
Enhanced activity
Enzyme inducers
Alcohol
Glucuronide and
Sulphate conjugates
60-90%
Cytochrome P450
5-10%
Hepatocyte
damage
Reactive metabolite
Glutathione
Depletion in
Malnutrition
Excretion
Replenish stores
N-acetlycysteine
Methionine

10. Case 1 25 year girl 30 paracetamol, 01.00am
PMH: epilepsy, on carbamazepine
Admitted 9.00am
Clinically well, obs normal
Para level: 80mg/L
Treat?

11. Treat???

12. Case 2 35yr male 60 paracetamol taken 24hours ago
O/E vomiting, abdo tender
P 120/min, BP 120/80
What else do you want to know?
What are you going to do?

13. Case 2 Blood glucose ABG, lactate PT U&Es, LFTs, Amylase
Paracetamol level
Urine output
Other medication?
Suicidal intent?, family support?

14. Case 2
PT 24
Bili 30, ALP 130, ALT 9000, Alb 40
Na 145, K 3.0, Ur 19, Cr 190
Glu 3.5
pH 7.38, O2 13, CO2 3, HCO3 12
Lactate 3.0

15. Management of paracetamol overdose
Monitor paracetamol levels > 4 hours after ingestion
If below treatment line, repeat level
Give NAC if over treatment line
?high risk line
Treatment lines not valid for staggered OD
If in doubt, give NAC! Don’t wait!

16. Monitor PT, creatinine, amylase, lactate, pH, LFTs daily
If abnormal, PT twice daily
iv fluids – patients will be dry!
Seek precipitating factors for overdose

17. Other management
If features of liver failure develop, continue N-acetylcysteine
PPI
Careful monitoring of fluid balance (CVP/U.O), haemodynamics
Broad spectrum antibiotics (anti-fungals)
Monitor and correct electrolytes (Ca, Mg, PO4)
Monitor glucose
Look for signs of confusion

18. Acute liver failure Support CNS Respiration Circulation Renal
Coagulation
Infection
Metabolism

19. Indications for liver transplant
pH < 7.3
lactate > 3.2
PT > 180
creatinine > 300+PT >100 +grade 3 or 4 coma prognosis very poor

20. Alcohol withdrawal

21. Alcohol Withdrawal Signs and symptoms range widely
tremulousness (shakes), insomnia, anxiety, hyperreflexia, mild autonomic hyperactivity, and GI upset
Delerium Tremens usually > 48 hours after cessation of drinking
Disorientation, agitation, and hallucinations; with severe autonomic hyperactivity (tremulousness, tachycardia, tachypnoea, hyperthermia)
Hallucinations
Persecutory, auditory, or (most commonly) visual and tactile hallucinations
Seizures

22. History Physical symptoms Moods/state of mind Morning drinking habits
Degree (and longevity) of drinking
Any suggestion of withdrawal symptoms

23. Severity of alcohol dependence questionnaire (SADQ)
Physical withdrawal symptoms
Affective withdrawal symptoms
Relief drinking
Frequency

24. CAGE questionnaire
Have you ever felt you should cut down on your drinking?
Have people annoyed you by criticising your drinking?
Have you ever felt bad or guilty about your drinking?
Have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover (eye-opener)?

25. Chlordiazepoxide Benzodiazepine
Controls symptoms of alcohol withdrawal
Patients admitting to >10u per day are likely to require treatment
Dose/level and length of treatment will depend on severity of dependence and on patient factors

27. Adverse effects Drowsiness, sedation Unsteadiness, ataxia Confusion
Dizziness, vertigo, syncope
Usually dose related
More common in elderly or in patients with liver disease

28. Wernicke’s encephalopathy
Thiamine deficiency
Classic triad of encephalopathy, ataxia, and ophthalmoplegia (10%)
Consider diagnosis:
long-term alcohol abuse or malnutrition
acute confusion, decreased conscious level, ataxia, ophthalmoplegia, memory disturbance, hypothermia with hypotension, and delirium tremens

29. Wernicke’s encephalopathy
Beware of administering dextrose in a thiamine-deficient state
Exacerbates the process of cell death by providing more substrate for biochemical pathways that lack sufficient amounts of coenzymes
Start thiamine concurrently or prior
Iv pabrinex (vitamins B + C)
2 pairs tds for 3 days
Thiamine 100mg tds
Vitamin B co forte 2 tabs daily

30. Korsakoff psychosis
Characterized by retrograde amnesia (inability to recall information),
Inability to assimilate new information
Decreased spontaneity and initiative
Confabulation.
Other manifestations of thiamine deficiency
Wet beri beri
Nutritional polyneuropathy

31. Chronic liver disease What pain relief can I give? Diuretics
The confused liver patient
What do I do
Role of sedatives?

32. Case You are called to see the following man who is c/o abdominal pain
48yr man, alcoholic liver disease
Bili 150, Alb 30, PT 16
Ascites

33. What concerns me? What is the cause of his pain? Renal function?
Has SBP been excluded?
Would a paracentesis relieve his pain?
Renal function?
Varices?
Encephalopathy?

34. Consider the analgesic options
Paracetamol?
NSAIDS?
Codeine?
Stronger Opiates?

35. Analgesia in chronic liver disease
Paracetamol
Safe in small quantities
Probably the safest analgesic for these patients!!!!
Reduce maximum daily intake and avoid regular dosing for >5 days)
ie 500mg – 1g qds prn (max 2g daily)

36. NSAIDs Codeine/Tramadol NEVER! Variceal haemorhage, renal failure
Risk of encephalopathy
Need to balance risk versus need for analgesia
Co-prescribe lactulose
Use lower doses, avoid regular dosing

37. Stronger opiates
Never without consultation with consultant in charge of patient
High risk of over-sedation and encephalopathy
Effects may be delayed/prolonged

38. Diuretics Why do we prescribe? To control ascites?
Why do we need to control ascites?
Patient comfort!
(Rarely respiratory distress)
REMEMBER:
Ascites does not kill patients, but diuretics can!

39. Which diuretic and why? Spironolactone Dose is 100 -200 mg once daily
Liver disease is a cause of secondary hyperaldosteronism
Aldosterone inhibitor
Dose is mg once daily
No need to split doses
Contraindications?
Hyperkalaemia, hyponatraemia
Renal impairment
Use cautiously and monitor closely!

40. The Confused Liver Patient
Consider:
Encephalopathy
Grades 1-4 (daytime somnolence, agitation, liver flap, decreased conscious level, coma)
Alcohol withdrawal
Sub-dural haematoma or other neurological event

41. Encephalopathy - causes
Drugs (including alcohol)
Check drug chart for night sedation, opiates, chlordiazepoxide
Electrolyte abnormalities
Low sodium, low potassium, dehydration
Hypoglycaemia
Sepsis (including SBP)
Constipation (Give lactulose + enemas)
GI bleeding

42. The home run! Take home points

43. Take home points (Paracetamol OD)
Para OD = Parvolex
PT is most sensitive indicator of liver injury
Careful attention to fluid balance
Early discussion!

44. Take home points (Alcohol withdrawal)
Take a proper alcohol history
Think about alcohol withdrawal before symptoms develop
Monitor patient daily and review dosage of chlordiazepoxide!
All dependent patients must receive Pabrinex and vitamin B.

45. Take home points (Analgesia in CLD)
Paracetamol is safe in small quantities and should be first choice
Caution with other groups
Diuretics
Think carefully before prescribing
No urgency in this situation
Monitor electrolytes and renal function

46. Confused liver patients
Management of encephalopathy is usually straightforward if you remember the checklist!
Check for sepsis
Lactulose
Fluids
Replace electrolytes
Check drug chart
Do not sedate them!!

47. Thank you for your attention!