Drug Handling in Liver Dysfunction

Penny North-LewisPaediatric Liver PharmacistSt James’s University HospitalJanuary 2010

Aim

To provide an approach to drug usage and dosing decisions in palliative patients with liver dysfunction

Plan for session

Introduction to the issuesBasic hepatologyHow you link this to drug handlingWorkshop

Problems with prescribing in liver dysfunction

Poor understanding of liver dysfunctionLack of information in regular sources

e.g BNF, SPC (misinformation/lack of data)

No easy equation to useLack of research, small numbers of

patients

Back to first principles

Need to know what type of liver disease your patient has and estimate the extent of liver dysfunction

Need to consider what drug factors will affect use in a patient with liver dysfunction e.g pharmacokinetics and side effect profile

Need to put the two together and decide Can the drug be used at all? Are their any specific precautions to use? What dose should be given?

Plan for session

Introduction to the issuesBasic hepatologyHow you link this to drug handlingWorkshop

Where is the liver?

In a child it can be felt 1-2cm below the ribcage.

In adults it can only be felt if it is enlarged

RUQ pain if enlarged

What does the liver do?

Synthesis (e.g. albumin & clotting factors)

Homeostasis e.g. glucose

Lipid Metabolism e.g. cholesterol

Bile production and secretion

Filtration e.g. antigens

Metabolism e.g drugs, oestrogens, toxic products such as ammonia

Some terminology used in liver disease

AcuteSudden onset – jaundice to

encephalopathy in less than 7 days (hyperacute), 28 days (acute), 6 months (sub-acute)

ChronicExtended duration – months/years

Some terminology used in liver disease

HepatocellularFatty infiltration (steatosis) e.g. alcohol Inflammation (hepatitis) e.g. viralCell death (necrosis) e.g. POD

Cholestasis Static bile flow (not specifically bilirubin)

Cholestasis

Extrahepatic

Intrahepatic

Some terminology used in liver disease

Ongoing damage:

Hepatocellular and cholestasis

initially

Throughout hepatocytes Biliary system

FibrosisAn increase in connective tissue in the liver – reversible

Some terminology used in liver disease

CirrhosisWidespread disorganised nodules in the liver

combined with fibrosis

Compensated cirrhosisWhen a cirrhotic liver continues to function

Decompensated cirrhosisWhen a cirrhotic liver can no longer function

adequately – signs eg coagulopathy occur

Liver OesophagusStomach

Spleen

Kidney

Splenic veinPortal Vein

Inferior vena cava

Portal hypertension

Liver conditions seen in palliative care??

End stage chronic liver disease / cirrhosisCoagulopathy, encephalopathy, ascites,

bleeding varicesCancer – liver primary or mets

Intra- or extra-hepatic cholestasis, pruritusIncidental liver dysfunction or disease

E.g cardiac failure, prolonged hypoxiaLiver disease unrelated to palliation

Plan for session

Introduction to the issuesBasic hepatologyHow you link this to drug handling

Liver testsSigns of liver diseaseDrug handling

Workshop

Drug handling in a liver patient -first principles

Liver Test Results

Signs of Liver Disease

Drug Characteristics

e.g. pharmacokinetics and side effects

The patient

Diagnosis

Knowing this helps!Liver dysfunction is a continuum – mild

to severe – depending on disease and stage.

Transaminases (0-35iu/L)(ALT & AST)

Enzyme released from hepatocytes when damaged

Markers of hepatocellular injury High elevations in acute injury (in several

thousands) Can be normal in severe chronic liver disease

(cirrhosis)Also found in heart, muscle and kidneyALT more specific to liver than AST

Bilirubin (3-17 micromol/l)

Product of erythrocyte breakdown

Conjugated in liver to form water soluble version which can be excreted

Plasma levels >50micromol/L give jaundice

Haem of erythrocytes

bilirubin

plasma

albumin (unconjugated)

hepatocyte (conjugated & water soluble)

bile

faeces

Causes of Hyperbilirubinaemia

Unconjugated Increased production Decreased uptake Decreased

conjugation Conjugated

Intrahepatic cholestasis

Extrahepatic cholestasis

Haem of erythrocytes

bilirubin

plasma

albumin (unconjugated)

hepatocyte (conjugated & water soluble)

bile

faeces

Alkaline Phosphatase (normal range varies for age and hospital)

Biliary enzyme – raised with bile duct damage Increased in cholestasis

Less raised in hepatocellular diseaseNot specific to the liver

also found in bone (eg raised in Paget’s disease/bone metastases)

small quantities in the intestine and placenta

Gamma glutamyl transferase (GGT) (0-30u/l)

Enzyme in biliary tract

Increased in cholestasis

Increased by enzyme inducing drugs

e.g. rifampicin and alcohol

Useful to determine if isolated raised

alkaline phosphatase is liver related

Albumin (37-49g/l)

Synthesised in liver

Half-life approx 20 days

Good indicator of chronic liver disease

Low specificity

Decreased intake e.g. malnutrition

Increased loss e.g. enteropathy

Prothrombin Time (~13 secs) or INR (0.9-1.2)

Decreased synthesis of clotting factors (cirrhosis)

Vitamin K malabsorption (in cholestasis)

Elevation > 3 seconds significant

Prolonged in acute & chronic liver disease

Useful prognostic indicator of impending liver failure e.g. acute liver failure or decompensated chronic liver disease

OR

Other useful tests

Ultrasound – liver texture, dopplers for blood flow in hepatic artery, portal vein

Liver biopsy – fibrosis, cirrhosis, intrahepatic cholestasis

OGD – varicesHIDA – bile flow (cholestasis)Blood glucose, creatinine

Drug handling in a liver patient -first principles

Liver Test Results

Signs of Liver Disease

Drug Characteristics

e.g. pharmacokinetics and side effects

The patient

Signs of liver disease

Jaundice Pale stools/dark urine Palmar erythema White nails Gynaecomastia/testicular

atrophy Spider naevi Ascites Bruising and bleeding Splenomegaly Oesphageal and gastric varices Encephalopathy

Ascites

“Spiders”

Jaundice

Useful tips on interpreting LFTs

Not all LFTs are specific to the liverLFTs alone DO NOT provide a diagnosis As a guide , a significant change =

>double upper limit of normalSome values may be within normal

ranges in chronic severe liver diseaseDifferent hospitals have different ranges

Useful tips on interpreting LFTs

Cholestasis↑ ↑ Alk Phos, ↑GGT, ↔ to ↑SBr

Hepatitis↑ to ↑ ↑ ↑ ALT↔ to ↑ INR, (↔ to ↑Alk Phos and SBr)

Cirrhosis↔ to ↑ALT, ↔ to ↑INR, ↔ to ↑SBr, ↓AlbuminWorsening if decompensated

Drug handling in a liver patient -first principles

Liver Test Results

Signs of Liver Disease

Drug Characteristics

e.g. pharmacokinetics and side effects

The patient

Absorption

Ascites may impair absorption e.g. diureticsBigger doses or IV

Cholestasis may impair absorption of fat soluble drugs e.g. fat soluble vitaminsBigger doses

Distribution

Ascites will increase volume of distribution for water soluble drugsBigger doses per kg

Low albumin will alter amount of free drug if highly protein boundReduced doses

Metabolism

Decompensated cirrhosis - reduced number of functioning hepatocytes Reduce dose or increase interval

Portal hypertension - reduced first pass metabolism if highly extracted drug e.g. propranolol, lidocaineReduce dose

Metabolism

Prodrugs that need to be metabolised to the active form in the liver may need bigger doses! E.g. enalapril

Elimination

Cholestasis – biliary cleared drugs may accumulate Caution if active/toxic metabolites are

produced, possibly not important if inactiveCompensatory pathways e.g. renal if

reduced biliary clearance?

Side Effect Profile

Drugs with the following side effects may need to be avoided/used with caution:

GI ulceration – varices, coagulopathy Constipation – cirrhosis, encephalopathy Pruritus - cholestasis Sedation – encephalopathy, cirrhosis Coagulation defects - coagulopathy Effects on electrolytes – cirrhosis, encephalopathy Effects on fluid balance – ascites, cirrhosis Renal toxicity - cirrhosis

Hepatotoxicity

Dose dependent (intrinsic e.g. paracetamol, methotrexate)

Dose independent (idiosyncratic) Usually acute, can be chronic Acute is usually in 5 to 90 days of starting drug Can occur after stopping causative drug Existing liver dysfunction does not increase

risk of hepatotoxic reaction

Drugs to avoid/use cautiously!!

NSAIDs Opioids Tricyclic antidepressants Benzodiazepines Antipsychotics Antimuscarinics Anticholinergics Long acting drugs unless carefully titrated and

pt stable

Drug Handling in liver impairment – in practice

Pharmacokinetic changes are not predictable

The liver has amazing capacity to continue to carry out functions even when cirrhotic

Need to be careful not to under dose patients for essential therapies e.g. chemotherapy and pain relief

Rule of thumb when prescribing in liver disease

Avoid or use certain drugs cautiously Avoid hepatotoxic drugs if possible Use therapeutic levels, where possible Monitor for efficacy eg BP, HR Monitor for toxicity Check renal function Use the smallest effective dose at the greatest

interval and titrate according to response

When do you need to worry?

Decompensated cirrhosis – encephalopathy, coagulopathy

Varices – risk of bleeding, effect on first pass metabolism

Ascites – Na content, fluid retentionCholestasis – if drug biliary clearedLow albumin – if highly protein bound

>90%

Plan for session

Introduction to the issuesBasic hepatologyHow you link this to drug handlingWorkshop

Review of common palliative drugsReview Rhee & Broadbent paperCases

Review of common palliative drugs

Analgesia Paracetamol Naproxen Codeine Tramadol Morphine Fentanyl

Drug Considerations Drug ….……………… Pharmacokinetics Considerations Absorption

Lipid solubilty (Absorption affected by ascites)

Distribution

Water/fat Protein binding % Displaced by bilirubin or displaces bilirubin

Metabolism First pass effect Hepatocyte dependent Prodrug CYPs Active metabolites Genetics

Elimination Biliary excretion Alternative mechanisms Enterohepatic recirculation (Renal impairment)

Side effects Consider – GI ulceration, sedation, coagulopathy, platelet effects, effects on fluid balance, effect on electrolytes, biliary sludging, renal impairment, constipation Hepatotoxicity - known hepatotoxin/type Published information in specific liver diseases/clinical studies BNF/SPC

Effect of drug on liver patient

HepatitisMild, normal INR and no chronic liver

diseaseCholestasis

Normal hepatocyte functionCirrhosis

Compensated but only just – INR 1.3-1.4, albumin 32, known varices, no encephalopathy

Paracetamol

Hepatic metabolism (multiple pathways) Need glutathione – stores may be reduced in the

severely malnourished

Hepatotoxic in overdose

oxidation conjugation with Mercapturic acid/ Paracetamol CYP2E1 NAPQI glutathione Cysteine acid conjugates

conjugation conjugation with protein

sulfhydryls

Glucuronide Sulphate

Complexes

Hepatotoxicity

Paracetamol

Use in mild hepatitis? Yes (caution alcoholics)

In cholestasis? Yes

In cirrhosis? YesReduce to TDS in severe decompensated

cirrhosis

Naproxen

Protein binding >99% Extensively hepatically metabolised ?biliary excretion Half life 12-15 hrs Side effects

GI ulceration Platelet inhibition Renal toxicity Fluid and electrolyte imbalance Hepatotoxicity

Naproxen

Use in hepatitis? Yes, normal dose. Caution hepatoxicity

In cholestasis? May displace bilirubin from protein binding sites Caution if deranged clotting from vit K

malabsorption Prefer avoid but could use with caution.

In cirrhosis? Poor metabolism, accumulation Bleeding risk, renal toxicity, fluid and electrlyte

disturbance AVOID

Codeine

First pass metabolism 50%Some biliary excretionHalf life 3-4 hrsPartial prodrug? Converted to morphineSide effects

Sedation, respiratory depressionConstipationPruritus

Codeine

Use in mild hepatitis? Yes – normal dose

In cholestasis? Possible impaired excretion Pruritus Yes – normal dose but use prn and monitor

In cirrhosis? Poor metabolism, possibly reduced efficacy as not

converted to morphine Sedation, respiratory depression High first pass metabolism – caution if varices Reduce dose and frequency and give laxatives

Dihydrocodeine may be better as parent drug exerts effect

Tramadol

Hepatic metabolism, first pass low Active intermediate metabolites No biliary excretion Half life 6 hrs Renal excretion 10%, increases to 30% in

cirrhosis Side effects

Lowers seizure threshold Plus usual opiate ADRs

Tramadol

Use in mild hepatitis? Yes, normal dose

In cholestasis? Yes, normal dose

In cirrhosis? Complex PK – parent partially active and slow

metabolism, intermediate active but slow to be formed and slow to clear - ?overall effect?

Use very cautiously – start low. Give laxatives

Morphine

Low protein bindingExtensive hepatic metabolism, first pass

>50%Biliary excretion and enterohepatic

recirculationHalf life 1-5 hrsSide effects

Sedation, respiratory depressionConstipationPruritus

Morphine

Use in mild hepatitis? Yes – normal dose

In cholestasis? Possible impaired excretion Pruritus, bile duct spasm Yes – normal dose but monitor and use prn

In cirrhosis? Poor metabolism, accumulation. Varices may affect

1st pass Sedation, resp depression – encephalopathy Caution reduce dose (to 25-50%) and frequency

Fentanyl

Protein binding 80%Large Vd – slow redistribution, only small

amt of drug available in central compartment

Half life not sig different in cirrhosis – long (redistribution t½ = 13 hrs)

Side effectsAs morphine, caution delayed effects

Fentanyl

Use in mild hepatitis? Yes – normal dose

In cholestasis? Yes – normal dose, poss increase pruritus

In cirrhosis? Metabolism only mildly impaired Sedation, resp depression – encephalopathy Can use – titrate carefully, caution with delayed

effects. Avoid patches – long acting and delayed absorption

Child-Pugh score – cirrhosis only

Score 1 2 3

SBr <34 34-51 >51

Albumin >35 30-35 <30

INR <1.7 1.7-2.3 >2.3

Ascites None Easily controlled

Poorly controlled

Encephalopathy None Minimal Advanced

A = 5-6 (mild), B = 7-9 (moderate), C ≥ 10 (severe)

Problems with literature

Rhee & Broadbent paperCritique – especially look at comments for

the drugs we have discussedAny other things stand out?

Cases

Key messages – when to worry

Cirrhosis, esp decompensated – encephalopathy, coagulopathy

Varices – risk of bleeding, effect on first pass metabolism

Ascites – Na content, fluid retentionCholestasis – if drug biliary clearedLow albumin – if highly protein bound

>90%

Key messages – generic rules

Work out what is wrong with your patient’s liver and how bad it is

See if the pharmacokinetics of the drug you want to use could be affected

Check the drug doesn’t have side effects which could harm the patient

Think!

Sources of further information

Medicines Q&As on NELMDrug PK data – Dollery, micromedex,

SPCDrugs and the Liver!

Caution with interpreting references