Drug Handling in Liver Dysfunction Penny North-Lewis Paediatric Liver Pharmacist St James’s...
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Transcript of Drug Handling in Liver Dysfunction Penny North-Lewis Paediatric Liver Pharmacist St James’s...
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