Safe drug use in patients with liver cirrhosis · Portal hypertension • Complications: varices (bleeding), encephalopathy ... Dicussion and conclusion by expert panel 5. Implementation

Safe drug use in patients with liver cirrhosis

Sander Borgsteede & Katja Taxis

Health Base Foundation, Houten, the Netherlands

University of Groningen – Unit of PharmacoTherapy, -Epidemiology & -Economics

Can I use this drug in a patient with cirrhosis?

o Increased risk for adverse drug reactionso 80% can probably be prevented

VorführenderPräsentationsnotizenChanged Pharmacokinetics and PharmacodynamicsRisk of Adverse drug reactions (30%) suffering of which 80% probably be prevented

Cirrhosis, pharmacokinetics and -dynamics

1. Liver disease and cirrhosiso Epidemiologyo Diagnosiso Most important symptoms

2. Pharmacokineticso Absorptiono Distributiono Metabolismo Elimination

3. Development of adviceso How did we develop evidence-based advices?o Examples how alert pop-up in the pharmacy

VorführenderPräsentationsnotizenInhoud praatje

Epidemiology

Bron: EASL - HEPAHEALTH project Report -2018

Diagnosis

Changes in liver architecture

o Scar tissue

o Nodules

Diagnosis: liver tests and severity of cirrhosisFirst question: does this patient have cirrhosis (biopsy/ Fibroscan)?

Laboratory tests Severity of cirrhosis (developed to predict prognosis)

Child-Turcotte-Pugh Score

Test Interpretation

Parenchymatic ASAT en ALAT Liver damage

Cholestatic tests Gamma-GT, AF en LDH Cholestasis

Liver function testsBilirubine Hepatic excretion

Prothrombin Time (PT) Hepatic synthesisAlbumine Hepatic synthesis

VorführenderPräsentationsnotizenPlaatje 1: Fibroscan®. Met een fibroscan meet je de snelheid waarmee geluidsgolven zich door de lever verplaatsen. Deze snelheid zegt wat over de mate van fibrose.

Symptoms

VorführenderPräsentationsnotizenSymptomen komen enerzijds door levercelfalen vs. veranderde doorbloeding

Portal hypertension• Complications: varices (bleeding), encephalopathy

• Transjugular Intrahepatic Portosystemic Shunt (TIPS)

Ascitis

• Fluid in peritonal cavity

VorführenderPräsentationsnotizenSplachnische vasodilatatie Verminderd arteriële vulling RAAS activatie natrium retentie in de nieren + H20(ook veranderde oncotische druk door verminderd albumine)

Hepatic Encephalopathy• Confusion induced by liver dysfunction

• Amonia is not detoxified

Cirrhosis and pharmacokinetics

Rikkers LF: Portal hypertension. In Miller TA [ed]: Physiologic Basis of Modern Surgical Care. pp. 417-428.

Absorption• Cirrose: ↓ First-pass effect• Liver shunting by varices/TIPS

Example: budesonide

Hempfling et al; Hepatol 2003;38:1

= cirrose

VorführenderPräsentationsnotizenBudesonide heeft een F= 10-15%; zeer groot first-pass effect. Als mogelijk is om ervoor te corrigeren; dan met name startdosering verlagenLate stage= cirrose

DistributionReduced synthesis of plasma proteins (e.g. albumine)

Ascites

Overall: the effect of distribution is limited Reduced protein binding (increased free fraction)

Increased distribution volume

VorführenderPräsentationsnotizenLagere hoeveelheden plasma-eiwitten/ meer bilirubine dat albumine bindt en mogelijk verandeirngen

MetabolismReduced enzyme activity in both phase I as phase II metabolism

Zowel fase I als fase II metabolisme aangedaan

VorführenderPräsentationsnotizenWaarschijnlijk zijn fase-1-reacties eerder aangedaan omdat deze oxidatief werken en zuurstof nodig hebben, welke aanvoer verminderd kan zijn bij cirrose.

Phase 1 metabolism

Johnson et al. Clin Pharmacokin; 2010;49(3):189-206.

VorführenderPräsentationsnotizenWaarschijnlijk zijn fase-1-reacties eerder aangedaan omdat deze oxidatief werken en zuurstof nodig hebben, welke aanvoer verminderd kan zijn bij cirrose. Deze grafiek zegt iets over het verloop van afname van werking van verschillende enzymen, het precieze effect blijft toch moeilijk te voorspellen.. Ook omdat het vaak moeilijk is te voorspellen waar in het traject de patiënt zich precies bevindt.

Grafiek1

Normale leverfunctieNormale leverfunctieNormale leverfunctieNormale leverfunctieNormale leverfunctieNormale leverfunctie

Child-Pugh AChild-Pugh AChild-Pugh AChild-Pugh AChild-Pugh AChild-Pugh A

Child-Pugh BChild-Pugh BChild-Pugh BChild-Pugh BChild-Pugh BChild-Pugh B

Child-Pugh CChild-Pugh CChild-Pugh CChild-Pugh CChild-Pugh CChild-Pugh C

CYP1A2

CYP2C19

CYP2C9

CYP2D6

CYP2E1

CYP3A4

Ernst levercirrose →

Fractie overgebleven activiteit enzym

1

1

1

1

1

1

0.63

0.32

0.69

0.76

0.74

0.59

0.26

0.26

0.52

0.33

0.48

0.39

0.12

0.12

0.33

0.11

0.11

0.25

Blad1

CYP1A2CYP2C19CYP2C9CYP2D6CYP2E1CYP3A4

Normale leverfunctie111111

Child-Pugh A0.630.320.690.760.740.59Studie Steelandt (uit Johnson) + Gonzalez

Child-Pugh B0.260.260.520.330.480.39Johnson

Child-Pugh C0.120.120.330.110.110.25

Blad1

CYP1A2

CYP2C19

CYP2C9

CYP2D6

CYP2E1

CYP3A4

Ernst levercirrose →

Fractie overgebleven activiteit/expressie van enzym

Excretion• Reduced biliary excretion• Compensated by increased renal excretion

• Risk for hepatorenal syndrome

VorführenderPräsentationsnotizenSommige gnm via gal uitgescheiden; deze hoeveelheid kan verminderd zijn. Vaak neemt nier deel over.Kan effect op entero-hepatische kringloop hebbenLet op bij complete biliare obstructie en cholestase. Sommige cytostatica worden voor een groot deel via de gal uitgescheiden en daar wordt vaak obv bilirubine of alkalisch fosfatase gedoseerd.

Pharmacodynamics• Difficult• Diuretics, sedatives• Anticoalugants

• Both synthesis and metabolism by the liver• Balans is very fragile

VorführenderPräsentationsnotizenHoge doseringen gebruikt bij ascites

To develop evidence-based recommendations on safe drug use in patients with liver cirrhosis

Can I use this drug in a patient with cirrhosis?

VorführenderPräsentationsnotizenChanged Pharmacokinetics and PharmacodynamicsRisk of Adverse drug reactions (30%) suffering of which 80% probably be prevented

1. Collection of evidence

2. Data extraction and presentation

3. Safety classification and dosage suggestion

4. Dicussion and conclusion by expert panel

5. Implementation

6. Continuity

VorführenderPräsentationsnotizenSPC + literaturePK alterations + safety dataImplementation: website + clinical decision support systemContinuity: new literature + comments from professionals

Safety class Description Action

Safe No increase in harm found Can be used

No additional risks known

No increase in harm foundbased on limited evidence Can be used

Additional risks known Increased harmLimited/ contradictory evidence Preferably use a safer drug

Unsafe Not safe in patients with liver cirrhosis. Avoid use

Unknown Insufficient data available Preferably use a safer drug

Depending on severity of cirrhosis Action is depending on severity of cirrhosis Retrieve severity of liver cirrhosis

www.geneesmiddelenbijlevercirrose.nlwww.drugsinlivercirrhosis.org

http://www.geneesmiddelenbijlevercirrose.nl/http://www.drugsinlivercirrhosis.org/

How does this work in the pharmacy?

• A patient has developed cirrhosis


Registration of a drug-disease interaction / contra-indication• From now on, an alert will be given for relevant medication


An alert pops up, with a specific advice

• Do not dispense. Consult the prescriber to prescribe alternative drug.


An alert pops up, with a specific advice

• Also an advice is given in case of a ‘safe’ drug: this drug can be usedby patients with cirrhosis


Questions

• [email protected]

• www.geneesmiddelenbijlevercirrose.nl (Dutch)• www.drugsinlivercirrhosis.org (limited number of drugs)


mailto:[email protected]://www.geneesmiddelenbijlevercirrose.nl/http://www.drugsinlivercirrhosis.org/

Safe drug use in patients with liver cirrhosisCan I use this drug in a patient with cirrhosis?Cirrhosis, pharmacokinetics and -dynamicsEpidemiologyEpidemiologyDiagnosisDiagnosis: liver tests and severity of cirrhosisSymptomsPortal hypertensionAscitisHepatic EncephalopathyCirrhosis and pharmacokineticsAbsorptionExample: budesonideDistributionMetabolismPhase 1 metabolismExcretionPharmacodynamicsFoliennummer 20Can I use this drug in a patient with cirrhosis?Foliennummer 22Foliennummer 23Foliennummer 24Foliennummer 25How does this work in the pharmacy?Registration of a drug-disease interaction / contra-indicationAn alert pops up, with a specific adviceAn alert pops up, with a specific adviceQuestions

Documents

Safe drug use in patients with liver cirrhosis · Portal hypertension • Complications: varices (bleeding), encephalopathy ... Dicussion and conclusion by expert panel 5. Implementation