drug & liver

8/14/2019 Drug & Liver

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To outline the livers role inthe following processes:

Protein handling Carbohydrate handling

Lipid handling Bile and bilirubin handling Hormone inactivation

Drug metabolism Immunological function


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HOW TO ASSESS THE LIVERFUNCTION ?

PLEASE ANSWER


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Principles of drug use in liverdisease


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Pharmacokinetics andpharmacodynamics

Adverse effects

Interactions


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l i


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Can you use paracetamol ina patient with liver

disease? YES OR NO?

Many people would answer no,perhaps because of the worriesabout paracetamol hepatotoxicity.

The answer, however, is most likelyto be

yes, but in actual fact you cannotanswer it without knowing more

about the patient.


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CASE STUDIES

Patient 1 Mild hepatitis withoutPatient 1 Mild hepatitis withoutcirrhosiscirrhosis

Non-alcoholic steatohepatitisNon-alcoholic steatohepatitis

The synthetic and metabolic capacityof this patients liver is unlikely tobe affected by the isolated rise inALT and drug handling is unlikely to

be altered.

It is important to ensure that thepatient has no signs of cirrhosis, as

many diseases that present with


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LETS TALK ABOUT CHOICE OFANALGESIC


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Paracetamol Paracetamol can safely be given to this

patient in normal therapeutic doses. If this patient was alcoholic or malnourished it

might raise additional concerns. Informationregarding the therapeutic use of paracetamolin alcoholics is limited and conflicting.

Considering the evidence available, currentpractice is not to reduce the dose ofparacetamol in alcoholics. However, if thepatient were malnourished a dose reductionmight be considered.

If the patient had acute viral hepatitis withsignificantly raised transaminases and a raisedPT, an increase in the dosage interval ofparacetamol should be considered as the

clearance of paracetamol has beenshown to


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Non-steroidal anti-inflammatorydrugs (NSAIDs)

NSAIDs can be used in this patient at

normal therapeutic doses. Given the rare but potential

hepatotoxic risk with NSAIDs, patients

should be instructed to be aware ofthe symptoms of hepatotoxicity and

to report fatigue, malaise, anorexia,nausea and vomiting.


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Opioids Opioids can be used in this patient at

normal therapeutic doses. If the patient had acute viral

hepatitis with significantly raisedtransaminases, an increase in the

dosage interval of pethidine shouldbe considered as the clearance ofpethidine has been shown to bereduced by approximately 50% in

these types of patients.


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HOW ABOUT LIPID

LOWERINGDRUGS?


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Statins Although the ALT is slightly higher than

three times ULN, a statin could be usedwith great caution.

However, as statins can cause raised ALTand AST, their use may make it difficult

to distinguish between iatrogenicelevation of ALT and AST and worseninghepatitis.

The statin should be started at a low doseand increased according to clinicalresponse.

There is no specific recommendation in

relation to which statin should be used.


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Bile acid sequestrants

Colestyramine and colestipol couldbe used in this patient providedthey are not constipated.

The INR should be routinelymonitored in case vitamin K

absorption is inhibited.


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Fibrates

Fibrates occasionally cause derangedLFTs: elevated ALT/AST, altered ALPand GGT.

Use of a fibrate may make it difficultto distinguish between iatrogenicelevation of ALT and AST and

worsening hepatitis.


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Ezetimibe

Ezetimibe has caused elevations intransaminases when used withsimvastatin,

with which it is usually combined.


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Inhibitors of fasting-inducedlipolysis

Acipimox is not associated with liveradverse drug reactions and shouldbe safe to use.

Niacin (nicotinic acid) has beenreported to cause transientelevation in transaminases at high

doses, as well as more serioushepatic reactions.

The SR form could be used with

caution.

P ti t 2 Ch l t iP ti t 2 Ch l t i


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Patient 2 CholestasisPatient 2 CholestasisPrimary sclerosing cholangitisPrimary sclerosing cholangitis

The synthetic and metabolic capacity ofthis patients liver is unlikely to beaffected by cholestasis.

However, consideration needs to begiven to

protein binding (the patient hashyperbilirubinaemia); excretion of thedrug or metabolites in bile (the

patient has cholestasis); and The lipophilicity of the drug (some

lipophilic drugs require bile salts forabsorption, and these would be

reduced in cholestasis).


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P a ra ce ta m o lPa ra ce ta m o l ca n b e sa fe lya d m in iste re d to th is p a tie n t in

n o rm a l th e ra p e u tic.d o s e s


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NSAIDs

Many centres prefer to avoid using

NSAIDs

However, if the liver disorder ispurely cholestatic in origin and the

disease has not progressed tocirrhosis and portal hypertension,NSAIDs may be an option.


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other types of patients who arechronically cholestatic may have

impaired absorption of vitamin Kand a raised INR. In these types ofpatients there is an increased riskof bleeding, and NSAIDs should

therefore be avoided.

WHY ?

PLEASE ANSWER


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Cholestasis may reduce the absorptionof the highly lipophilic ibuprofen.

All NSAIDs are highly protein bound andincreased levels of free drug may occurin the presence of a raised bilirubin,because it can displace the bound drugfrom albumin.

The metabolism of NSAIDs is unlikely tobe affected in this patient. Cholestasis may reduce the elimination

of certain NSAIDs that are excreted via

the biliary tract (e.g. sulindac,indometacin). Ibuprofen is associated with the lowest

risk of GI bleeding compared toother

NSAIDs.Wh a ain ?


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Taking into accountpharmacokinetics, adverse effects

and clinical studies, ibuprofen may be considered the

best choice in this patient, for the

following reasons: Short half-life

No biliary excretion of active forms

Possibly the lowest risk ofhepatotoxicity

Lowest risk of bleeding when used

at doses


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O p io id sp io id s ca n b e u se d w ith ca u tio n a s .e ta b o lism is n o t a ffe cte d in th is p a tie n t C a re.u st b e ta k e n to a v o id co n stip a tio n o st o p io id s h ave lo w lip id so lu b ility an d are.e ll a b so rb e d o ra lly in ch o le sta sis ,o st o p io id s h a v e lo w p ro te in b in d in g solte ra tio n s in a lb u m in a n d b iliru b in a re u n like ly.o a lte r fre e d ru g le v e ls h o le sta sis m a y re d u ce th e e lim in a tio n o f,o rp h in e a n d p o ssib ly co d e in e a s th e y.n d e rg o so m e b ilia ry e x c re tio n

o rp h in e ca n re d u ce b ilia ry se c re tio n s a n d,a n ca u se b ile d u ct sp a sm w h ich co u ld ca u se,e d u ced b ilia ry flo w p o te n tia lly e xa ce rb a tin g .h is p a tie n t s p ro b le m s n p ra ctice th is d o e s n o t a p p e a r to b e.lin ica ll si n ifica n t


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It is important to note that the patientcould rapidly deteriorate into a state of

decompensation where liver functionwould be markedly affected.

Other things to consider are the

raised INR and low platelet count (avoid drugs that affect

coagulation or cause bleeding), the riskof

encephalopathy if the liver functiondecompensates (caution with anydrugs causing sedation, constipation,fluid or electrolyte disturbances) andthe

risk of hepatorenal syndrome (avoid


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Statins In 2006 the National Lipid Associations

Statin Safety Assessment Task Forceconcluded that chronic liver disease andstable, compensated liver disease arenot contraindications to the use ofstatins [2, 3].

However, statins should be used withcaution in this patient for two reasons:

They are highly excreted in bile andtheir pharmacodynamic disposition in

obstructive cholestasis is unknown. They are highly protein bound, and

hyperbilirubinaemia may result inincreased blood levels of free drug and

metabolites through displacement from-


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Colestyramine and colestipol couldbe used in this patient providedthere is no constipation.

The INR should be routinelymonitored in case vitamin Kabsorption is inhibited.

These drugs might have a beneficial

effect on the pruritus.


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Fibrates

The fibrates are very lipophilic & highly proteinbound.

Hyperbilirubinaemia may cause displacementfrom plasma proteins, leading to increased freedrug concentrations.

Fenofibrate and bezafibrate are excreted almost

entirely in the urine and are more appropriatethan gemfibrozil in obstructive jaundice.

Gemfibrozil is significantly excreted in bile andundergoes enterohepatic recycling, to whichpart of its activity is due; this would be reduced

by obstructive jaundice. All fibrates can cause an increase in the

cholesterol saturation of bile. An increase ingallstone formation has been reported.This is aclass effect.

The fibrates may cause altered LFTs, including


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Ezetimibe Ezetimibe is highly lipid soluble but it is

not clear whether it requires bile salts

for absorption. Part of its activity is due to enterohepatic

recycling, which may be reduced byobstructive jaundice.

This may lead to a reduction in, or theelimination of, any secondary peaks.

It is highly plasma protein bound:hyperbilirubinaemia may cause

displacement from plasma proteins,leading to increased free drugconcentrations.

It has not been reported to cause

cholestasis. However, it is generallyused with simvastatin which would not


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Inhibitors of fasting-inducedlipolysis

As acipimox and niacin are not highlyprotein bound and are notlipophilic,

cholestasis should not affect theirdisposition.

They are largely excreted in the

urine. Neither has been reported tocause cholestasis.

Both may cause pruritus, from which

this patient suffers.


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Drug interactions

Fluvastatin has been reported tointeract with rifampicin, causingincreased clearance of the statin.

Rifampicin is an inducer of the CYP

450 3A4 isoenzyme and mayincrease the rate of clearance ofstatins that are substrates for 3A4.


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cirrhosiscirrhosisCryptogenic cirrhosis

Despite cirrhosis, this patient ismaintaining good hepatocyte function

(normal albumin, mildly raised INR,normal bilirubin) and the metabolic and

excretory capacity of the liver shouldnot be significantly reduced.

The patient has portal hypertension, soblood flow to the liverwill be impaired,

which will reduce first-pass metabolismof highly extracted drugs (extractionratio >0.7).

This will result in greater bioavailability of

oral doses of these drugs.


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P a ra ce ta m o l Pa ra ce ta m o l ca n sa fe ly b e a d m in iste re d in n o rm a l

.th e ra p e u tic d o se s in th is p a tie n t C a u tio n sh o u ld b e u se d in p a tie n ts su sce p tib le to

h e p a tic e n zym e in d u ctio n( . . -e g chronic alcoholics and patients taking enzyme

).in d u cin g d ru g sE n zym e in d u ctio n m a y th e o re tica lly e n h a n ce th e

p ro d u ctio n o f tox ic,m e ta b o lite s b u t cu rre n tly th e re is n o cle a r e vid e n ce

.th a t th e se in te ra ctio n s a re clin ica lly sig n ifica n t C u rre n t e vid e n ce su g g e sts th a t ch ro n ic a lco h o lic

p a tie n ts can b e g ive n p a ra ce ta m o l in n o rm a l

,th e ra p e u tic d o ses a s u n le ss th e y h a v e o th e r risk,fa cto rs su ch a s m a ln u tritio n th e ir risk o f d e ve lo p in gse v e re h e p a to tox icity is n o g re a te r th a n th a t o f th e

.g e n e ra l p o p u la tio n C a u tio n sh o u ld b e u se d in p a tie n ts w ith re d u ce d

a b ility to e lim in a te th e toxic m e ta b o lite d u e to


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NSAIDs

NSAIDs should be avoided in thispatient, or indeed any patient withcirrhosis, because of theirunfavourable side-effect profile:

Increased risk of bruising/bleedingIncreased risk of renal dysfunctionand hepatorenal syndrome

Increased risk of gastrointestinalulceration (especially if takenconcomitantly with alcohol)

Disturbance of electrolytes and fluid

balance.


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Opioids

Ideally opioids should be avoided in

this patient as most aremetabolised by the liver and have ahigh first-pass effect (exceptionsinclude tramadol).

Strong opioids

These should only be considered insevere pain, preferably afterdiscussion with a liver unit.


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Tramadol

Should not be considered first line in cirrhotic patientsfor the following

:reasons Tramadol itself acts on the neurotransmitters

,norepinephrine and serotonin whereas the activeintermediate metabolite acts on opioid receptors and has a

.much higher affinity for these than tramadol

If metabolism is reduced the analgesic effect provided bythe active

.metabolite would be expected to decrease -The half life of tramadol and its active metabolite willbe increased

( )owing to reduced clearance so the overall effect ontramadol activity is.not known

,Tramadol can lower the seizure threshold which could

precipitate . . .seizures in susceptible individuals e g alcoholics


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Statin

compensated liver disease are not

contraindications to the use of statins, but contraindicated in decompensated disease

or liver failure

As the patient has portal hypertension,blood flow through the liver is reducedand the first-pass effect is likely to belessened, increasing the amount of allstatins reaching the systemic circulation.

a statin is necessary, the drug of choicewould be pravastatin which undergoesless first-pass extraction and is only partlycleared by the liver

should be started at a low dose, e.g. 10 mg


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Colestyramine and colestipol couldbe used provided the patient is not

constipated.


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FibratesFibrates can cause derangements ofLFTs, both cholestatic (GGT and ALP)and hepatitic (AST, ALT).

This may be difficult to distinguish froman endogenous change in the patientsliver picture.

The fibrates have been reported to causea reduction in haemoglobin, whichmight be - significant in this patient, asshe has thrombocytopenia and onevarix:

Fenofibrate can also reduce fibrinogenlevels. Fibrates should therefore be

avoided in this patient.


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Ezetimibe

Ezetimibe is only partly metabolisedby the liver and should be safe to

use alone.

Inhibitors of fasting-induced lipolysis


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Inhibitors of fasting induced lipolysis

Acipimox is only partly metabolised andshould be safe in this patient.

Niacin undergoes extensive first-passmetabolism, which would be reduceddue to the decrease in liver blood flow

caused by the patients cirrhosis. Both drugs are gastric irritants and should

probably be avoided in patients with

varices or a history of variceal bleedingor coagulopathy, or a risk thereof.

Niacin can also cause thrombocytopenia.

This patient has a varix and would be at

Patient 4 DecompensatedPatient 4 Decompensated


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Patient 4 DecompensatedPatient 4 Decompensatedcirrhosiscirrhosis

Alcoholic liver disease

This patient has decompensated liver disease withsignificantly impaired synthetic, metabolic andexcretory function (low albumin, raised INR,hyperbilirubinaemia, encephalopathy).

The reduction in hepatocyte mass and function will

significantly reduce the metabolism of low extractionratio drugs (hepatocyte dependent).

The patient also has severe portal hypertension, whichwill reduce first-pass metabolism, increasing thebioavailability of high extraction ratio drugs.

The ascites may alter the absorption and distribution ofsome drugs.

Highly protein-bound drugs may be affected byhypoalbuminaemia and hyperbilirubinaemia, resulting

in increased levels of free drug.


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Other things to consider are the

raised INR (avoid drugs that affect coagulation or cause

bleeding), encephalopathy (avoidany drugs

causing sedation and other CNS sideeffects, constipation, fluid or

electrolyte disturbances) andimpaired renal function (adjustdoses

accordingly and avoid renally toxic

drugs).


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Paracetamol

The half-life has been shown to beprolonged in some single-dose

studies, but no accumulation orhepatotoxicity has been shownafter

repeated dosing, therefore normaldoses and frequency can be used.

Further advice as for Patient 3 withcompensated cirrhosis.


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NSAIDs NSAIDs should be avoided in

decompensated cirrhotic patientsbecause

of the potential for impairedmetabolism and increases in the levelof

unbound drug due to low albumin andhigh bilirubin, but more importantly

NSAIDs should be avoided because oftheir unfavourable sideeffect

profile (see details in Patient 3).


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Opioids analgesic

Ideally opioids should be avoided inthis patient, as most are

metabolisedn by the liver

so there is a risk of accumulation inhepatic cirrhosis and portal

hypertension.


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Patient 5 Acute liverPatient 5 Acute liver


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Patient 5 Acute liverPatient 5 Acute liverfailurefailure

Paracetamol overdose This patient has markedly impaired hepatocyte functionand hence reduced metabolic and excretory capacity(raised INR, hyperbilirubinaemia,encephalopathy).Low extraction drugs (hepatocyte dependent) are

likely to accumulate and should be used cautiously. The distribution of highly protein-bound drugs may be

affected by hyperbilirubinaemia, increasing theunbound fraction. Biliary excretion may be impaired.

Other things to consider are the raised INR (avoid drugs that affect coagulation or cause

bleeding), encephalopathy (avoid any drugs causingsedation, constipation, fluid or electrolytedisturbances) and impaired renal function.


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Paracetamol could be considered in apatient with acute liver failure

caused by something other than aparacetamol overdose.

Normal therapeutic doses of

paracetamol can be used, but it may be prudent to extend the

dosing interval in all patients withacute liver failure because

a reduced clearance has beendemonstrated in patients withacute viral hepatitis and a

prolonged PT.


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NSAIDs

NSAIDs should be avoided in anypatient with acute liver failure

because of their unfavourable side-effect profile.

Increased risk of bruising/bleeding

Increased risk of renal dysfunctionand hepatorenal syndrome

Increased risk of gastrointestinalulceration

Disturbance of electrolytes and fluidbalance.


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Opioids

In practice, the metabolism of opioids

appears to be well preservedduring periods of acute liverdysfunction, but the drugs are likely

to accumulate in prolongeddisease.

this patient has

grade III encephalopathy the use ofany opioid should be avoided ifpossible unless the patient isventilated.


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Lipid Lowering Drugs.

Patient 5 Acute liver failure

Unnecessary medications should bewithheld until the patients liver

function normalises and theirpharmaceutical needs arereassessed.


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WISHING YOU TO BE LUCKYWISHING YOU TO BE LUCKY WITHWITH

LIVER CASELIVER CASE ININ

COMING PROFESSIONAL IIICOMING PROFESSIONAL IIIEXAMEXAM

EST OF LUCK IN FINALEST OF LUCK IN FINALEXAMXAM

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