Drugs and prescribing in Drugs and prescribing in Liver diseaseLiver disease

Esther UnittEsther Unitt

Consultant HepatologistConsultant Hepatologist

ObjectivesObjectives

Paracetamol hepatotoxicityParacetamol hepatotoxicity Management of alcohol withdrawalManagement of alcohol withdrawal Chronic liver diseaseChronic liver disease

• What pain relief can I give?What pain relief can I give?• DiureticsDiuretics• The confused liver patientThe confused liver patient

What do I doWhat do I do Role of sedatives?Role of sedatives?

Paracetamol OverdoseParacetamol Overdose

Aetiology of Acute Liver Failure in UK and Europe.

UK Europe Paracetamol hepatotoxicity 54.1% 2%

Viral 36.5% 70%HAV 4.9% 4%HBV + HDV 9.0% 45%Other 0.6% 3%Indeterminate 16.5% 18%

Drug reaction 6.9% 14.5%

Miscellaneous 3.9% 12

Paracetamol as cause of acute liver Paracetamol as cause of acute liver failurefailure

Commonest cause of ALF in UK (>50%)Commonest cause of ALF in UK (>50%) Usually taken with suicidal intentUsually taken with suicidal intent 8% due to unintentional overdosing in ‘high risk’ 8% due to unintentional overdosing in ‘high risk’

patientspatients ALF occurs in 2-5% of patients who present ALF occurs in 2-5% of patients who present

following paracetamol ODfollowing paracetamol OD Median dose 40g (range 5-210g)Median dose 40g (range 5-210g)

ParacetamolParacetamol

Nausea/vomiting (after 24hours)Nausea/vomiting (after 24hours) RUQ pain/tendernessRUQ pain/tenderness

Liver damage maximal 3-4 days after Liver damage maximal 3-4 days after ingestioningestion• Encephalopathy, haemorrhage, Encephalopathy, haemorrhage,

hypoglycaemia, sepsis, cerebral oedema hypoglycaemia, sepsis, cerebral oedema and deathand death

TreatmentTreatment

N-acetylcysteine (Parvolex)N-acetylcysteine (Parvolex)

Metabolism of paracetamolMetabolism of paracetamol

Paracetamol

Reactive metabolite

Glucuronide andSulphate conjugates60-90% Cytochrome P450

5-10%

Glutathione

Hepatocyte damage

Excretion

Depletion inMalnutrition

Enhanced activityEnzyme inducersAlcohol

Replenish storesN-acetlycysteineMethionine

Case 1Case 1

25 year girl25 year girl 30 paracetamol, 01.00am30 paracetamol, 01.00am PMH: epilepsy, on carbamazepinePMH: epilepsy, on carbamazepine Admitted 9.00amAdmitted 9.00am Clinically well, obs normalClinically well, obs normal

Para level: 80mg/LPara level: 80mg/L Treat? Treat?

Treat???

Case 2Case 2

35yr male35yr male 60 paracetamol taken 24hours ago60 paracetamol taken 24hours ago O/E vomiting, abdo tenderO/E vomiting, abdo tender

• P 120/min, BP 120/80P 120/min, BP 120/80

What else do you want to know?What else do you want to know? What are you going to do?What are you going to do?

Case 2Case 2

Blood glucoseBlood glucose ABG, lactateABG, lactate PTPT U&Es, LFTs, AmylaseU&Es, LFTs, Amylase Paracetamol levelParacetamol level Urine outputUrine output Other medication?Other medication? Suicidal intent?, family support?Suicidal intent?, family support?

Case 2Case 2

PT PT 2424 Bili 30, ALP 130, ALT Bili 30, ALP 130, ALT 90009000, Alb 40, Alb 40 Na 145, K 3.0, Na 145, K 3.0, Ur 19, Cr 190Ur 19, Cr 190 Glu 3.5Glu 3.5 pH 7.38pH 7.38, O, O22 13, CO 13, CO22 3, HCO 3, HCO33 12 12 Lactate 3.0Lactate 3.0

Management of paracetamol Management of paracetamol overdoseoverdose

Monitor paracetamol levels > 4 hours after Monitor paracetamol levels > 4 hours after ingestioningestion

If below treatment line, repeat levelIf below treatment line, repeat level Give NAC if over treatment lineGive NAC if over treatment line

• ?high risk line?high risk line

Treatment lines not valid for Treatment lines not valid for staggered ODstaggered OD

If in doubt, give NAC! Don’t wait!If in doubt, give NAC! Don’t wait!

Monitor Monitor PTPT, creatinine, amylase, , creatinine, amylase, lactate, pH, LFTs dailylactate, pH, LFTs daily

If abnormal, PT twice dailyIf abnormal, PT twice daily iv fluids – patients will be dry!iv fluids – patients will be dry! Seek precipitating factors for Seek precipitating factors for

overdoseoverdose

Other managementOther management

If features of liver failure develop, If features of liver failure develop, continue N-acetylcysteinecontinue N-acetylcysteine • PPIPPI• Careful monitoring of fluid balance (CVP/U.O), Careful monitoring of fluid balance (CVP/U.O),

haemodynamicshaemodynamics• Broad spectrum antibiotics (anti-fungals)Broad spectrum antibiotics (anti-fungals)• Monitor and correct electrolytes (Ca, Mg, PO4)Monitor and correct electrolytes (Ca, Mg, PO4)• Monitor glucoseMonitor glucose• Look for signs of confusionLook for signs of confusion

Acute liver failureAcute liver failure

SupportSupport• CNSCNS• RespirationRespiration• CirculationCirculation• RenalRenal• CoagulationCoagulation• InfectionInfection• MetabolismMetabolism

Indications for liver transplantIndications for liver transplant

pH < 7.3 pH < 7.3 lactate > 3.2lactate > 3.2 PT > 180PT > 180 creatinine > 300+PT >100 +grade 3 creatinine > 300+PT >100 +grade 3

or 4or 4 coma prognosis very poor coma prognosis very poor

Alcohol withdrawalAlcohol withdrawal

Alcohol WithdrawalAlcohol Withdrawal Signs and symptoms range widelySigns and symptoms range widely

• tremulousness (shakes), insomnia, anxiety, tremulousness (shakes), insomnia, anxiety, hyperreflexia, mild autonomic hyperactivity, and GI hyperreflexia, mild autonomic hyperactivity, and GI upset upset

Delerium Tremens usually > 48 hours after Delerium Tremens usually > 48 hours after cessation of drinking cessation of drinking • Disorientation, agitation, and hallucinations; with severe Disorientation, agitation, and hallucinations; with severe

autonomic hyperactivity (tremulousness, tachycardia, autonomic hyperactivity (tremulousness, tachycardia, tachypnoea, hyperthermia) tachypnoea, hyperthermia)

HallucinationsHallucinations• Persecutory, auditory, or (most commonly) visual and Persecutory, auditory, or (most commonly) visual and

tactile hallucinationstactile hallucinations SeizuresSeizures

HistoryHistory

Physical symptomsPhysical symptoms Moods/state of mindMoods/state of mind Morning drinking habitsMorning drinking habits Degree (and longevity) of drinkingDegree (and longevity) of drinking Any suggestion of withdrawal Any suggestion of withdrawal

symptomssymptoms

Severity of alcohol dependence Severity of alcohol dependence questionnaire (SADQ)questionnaire (SADQ)

Physical withdrawal symptomsPhysical withdrawal symptoms Affective withdrawal symptomsAffective withdrawal symptoms Relief drinkingRelief drinking FrequencyFrequency

CAGE questionnaireCAGE questionnaire

Have you ever felt you should Have you ever felt you should cutcut down down on your drinking? on your drinking?

Have people Have people annoyedannoyed you by criticising you by criticising your drinking? your drinking?

Have you ever felt bad or Have you ever felt bad or guiltyguilty about about your drinking? your drinking?

Have you ever had a drink first thing in the Have you ever had a drink first thing in the morning to steady your nerves or get rid of morning to steady your nerves or get rid of a hangover (a hangover (eyeeye-opener)? -opener)?

ChlordiazepoxideChlordiazepoxide

BenzodiazepineBenzodiazepine Controls symptoms of alcohol Controls symptoms of alcohol

withdrawalwithdrawal Patients admitting to >10u per day Patients admitting to >10u per day

are likely to require treatmentare likely to require treatment Dose/level and length of treatment Dose/level and length of treatment

will depend on severity of will depend on severity of dependence and on patient factorsdependence and on patient factors

Adverse effectsAdverse effects

Drowsiness, sedationDrowsiness, sedation Unsteadiness, ataxiaUnsteadiness, ataxia ConfusionConfusion Dizziness, vertigo, syncopeDizziness, vertigo, syncope

Usually dose relatedUsually dose related More common in elderly or in More common in elderly or in

patients with liver diseasepatients with liver disease

Wernicke’s encephalopathyWernicke’s encephalopathy

Thiamine deficiencyThiamine deficiency Classic triad of encephalopathy, Classic triad of encephalopathy,

ataxia, and ophthalmoplegia (10%) ataxia, and ophthalmoplegia (10%) Consider diagnosis:Consider diagnosis:

• long-term alcohol abuse or malnutrition long-term alcohol abuse or malnutrition acute confusion, decreased conscious level, acute confusion, decreased conscious level,

ataxia, ophthalmoplegia, memory ataxia, ophthalmoplegia, memory disturbance, hypothermia with hypotension, disturbance, hypothermia with hypotension, and delirium tremensand delirium tremens

Wernicke’s encephalopathyWernicke’s encephalopathy

Beware of administering dextrose in a Beware of administering dextrose in a thiamine-deficient state thiamine-deficient state

Exacerbates the process of cell death by providing Exacerbates the process of cell death by providing more substrate for biochemical pathways that lack more substrate for biochemical pathways that lack sufficient amounts of coenzymessufficient amounts of coenzymes

Start thiamine concurrently or priorStart thiamine concurrently or prior Iv pabrinex (vitamins B + C)Iv pabrinex (vitamins B + C)

• 2 pairs tds for 3 days2 pairs tds for 3 days Thiamine 100mg tdsThiamine 100mg tds Vitamin B co forte 2 tabs dailyVitamin B co forte 2 tabs daily

Korsakoff psychosisKorsakoff psychosis

Characterized by retrograde amnesia Characterized by retrograde amnesia (inability to recall information),(inability to recall information),

Inability to assimilate new informationInability to assimilate new information Decreased spontaneity and initiativeDecreased spontaneity and initiative Confabulation. Confabulation.

Other manifestations of thiamine Other manifestations of thiamine deficiencydeficiency• Wet beri beriWet beri beri• Nutritional polyneuropathy Nutritional polyneuropathy

Chronic liver diseaseChronic liver disease

• What pain relief can I give?What pain relief can I give?• DiureticsDiuretics• The confused liver patientThe confused liver patient

What do I doWhat do I do Role of sedatives?Role of sedatives?

CaseCase You are called to see the following You are called to see the following

man who is c/o abdominal painman who is c/o abdominal pain 48yr man, alcoholic liver disease 48yr man, alcoholic liver disease Bili 150, Alb 30, PT 16Bili 150, Alb 30, PT 16 AscitesAscites

What concerns me?What concerns me?

What is the cause of his pain?What is the cause of his pain?• Has SBP been excluded?Has SBP been excluded?• Would a paracentesis relieve his pain?Would a paracentesis relieve his pain?

Renal function? Renal function? Varices?Varices? Encephalopathy?Encephalopathy?

Consider the analgesic optionsConsider the analgesic options

• Paracetamol?Paracetamol?• NSAIDS?NSAIDS?• Codeine?Codeine?• Stronger Opiates?Stronger Opiates?

Analgesia in chronic liver diseaseAnalgesia in chronic liver disease

ParacetamolParacetamol• Safe in small quantitiesSafe in small quantities• Probably the safest analgesic for these Probably the safest analgesic for these

patients!!!!patients!!!!• Reduce maximum daily intake and avoid Reduce maximum daily intake and avoid

regular dosing for >5 days)regular dosing for >5 days) ie 500mg – 1g qds prn (max 2g daily)ie 500mg – 1g qds prn (max 2g daily)

NSAIDsNSAIDs• NEVERNEVER! Variceal haemorhage, renal ! Variceal haemorhage, renal

failurefailure Codeine/TramadolCodeine/Tramadol

• Risk of encephalopathyRisk of encephalopathy• Need to balance risk versus need for Need to balance risk versus need for

analgesiaanalgesia• Co-prescribe lactuloseCo-prescribe lactulose• Use lower doses, avoid regular dosing Use lower doses, avoid regular dosing

Stronger opiatesStronger opiates

Never without consultation with Never without consultation with consultant in charge of patientconsultant in charge of patient• High risk of over-sedation and High risk of over-sedation and

encephalopathyencephalopathy• Effects may be delayed/prolongedEffects may be delayed/prolonged

DiureticsDiuretics Why do we prescribe?Why do we prescribe? To control ascites? To control ascites? Why do we need to control ascites?Why do we need to control ascites?

Patient comfort!Patient comfort! (Rarely respiratory distress)(Rarely respiratory distress)

REMEMBER: REMEMBER: Ascites does not kill patients, but diuretics Ascites does not kill patients, but diuretics can!can!

Which diuretic and why?Which diuretic and why?

SpironolactoneSpironolactone• Liver disease is a cause of secondary Liver disease is a cause of secondary

hyperaldosteronismhyperaldosteronism• Aldosterone inhibitorAldosterone inhibitor

Dose is 100 -200 mg once dailyDose is 100 -200 mg once daily• No need to split dosesNo need to split doses

Contraindications?Contraindications?• Hyperkalaemia, hyponatraemiaHyperkalaemia, hyponatraemia• Renal impairmentRenal impairment

Use cautiously and monitor closely!Use cautiously and monitor closely!

The Confused Liver PatientThe Confused Liver Patient

Consider:Consider:• EncephalopathyEncephalopathy

Grades 1-4 (daytime somnolence, agitation, Grades 1-4 (daytime somnolence, agitation, liver flap, decreased conscious level, coma)liver flap, decreased conscious level, coma)

• Alcohol withdrawalAlcohol withdrawal• Sub-dural haematoma or other Sub-dural haematoma or other

neurological eventneurological event

Encephalopathy - causesEncephalopathy - causes

Drugs (including alcohol)Drugs (including alcohol)• Check drug chart for night sedation, opiates, Check drug chart for night sedation, opiates,

chlordiazepoxidechlordiazepoxide Electrolyte abnormalitiesElectrolyte abnormalities

• Low sodium, low potassium, dehydrationLow sodium, low potassium, dehydration HypoglycaemiaHypoglycaemia Sepsis (including SBP)Sepsis (including SBP) Constipation (Give lactulose + enemas)Constipation (Give lactulose + enemas) GI bleedingGI bleeding

The home run!The home run!Take home pointsTake home points

Take home pointsTake home points(Paracetamol OD)(Paracetamol OD)

Para OD = ParvolexPara OD = Parvolex PT is most sensitive indicator of liver PT is most sensitive indicator of liver

injuryinjury Careful attention to fluid balanceCareful attention to fluid balance Early discussion!Early discussion!

Take home pointsTake home points(Alcohol withdrawal)(Alcohol withdrawal)

Take a proper alcohol historyTake a proper alcohol history Think about alcohol withdrawal Think about alcohol withdrawal

before symptoms developbefore symptoms develop Monitor patient daily and review Monitor patient daily and review

dosage of chlordiazepoxide!dosage of chlordiazepoxide! All dependent patients must receive All dependent patients must receive

Pabrinex and vitamin B.Pabrinex and vitamin B.

Take home pointsTake home points(Analgesia in CLD)(Analgesia in CLD)

Paracetamol is safe in small Paracetamol is safe in small quantities and should be first choicequantities and should be first choice

Caution with other groupsCaution with other groups DiureticsDiuretics

• Think carefully before prescribingThink carefully before prescribing• No urgency in this situationNo urgency in this situation• Monitor electrolytes and renal functionMonitor electrolytes and renal function

Confused liver patientsConfused liver patients

Management of encephalopathy is Management of encephalopathy is usually straightforward if you usually straightforward if you remember the checklist!remember the checklist!• Check for sepsisCheck for sepsis• LactuloseLactulose• FluidsFluids• Replace electrolytesReplace electrolytes• Check drug chartCheck drug chart

Do not sedate them!!Do not sedate them!!

Thank you for Thank you for your attention!your attention!