Effect of Cirrhosis on Drug Metabolism Mariam Alosfoor

Objectives

Introduction Normal liver metabolism. Liver disease and metabolism Dosage calculation in case of liver disease

Introduction Absorption

Liver Metabolis

mLiver

DiseaseBlood Flow

Protein Binding

Dosage Adjustmen

t

Introduction

Acute liver impairment interferes with drug metabolism and elimination.

Chronic liver impairment affects all parameters of pharmacokinetic.

Because most drugs are metabolized by the liver, it is susceptible to drug toxicity.

Impaired liver function greatly increases the risks of adverse drug effects.

Introduction Absorption

Liver Metabolis

mLiver

DiseaseBlood Flow

Protein Binding

Dosage Adjustmen

t

Introduction

General guidelines when using drugs include:

Clinical signs for hepatotoxicity should be sought (nausea, vomiting, jaundice, hepatomegaly).

Hepatotoxic drugs should be avoided if possible: (acetaminophen, INH, statins, methotrexate, phenytoin, aspirin and alcohol).

Introduction Absorption

Liver Metabolis

mLiver

DiseaseBlood Flow

Protein Binding

Dosage Adjustmen

t

Monitoring liver tests: Serum bilirubin levels above 4 to 5

mg/dl Prothrombin time greater than 1.5

times control Serum albumin below 2.0 g/dl Elevated alanine and aspartate

aminotransferases (ALT & AST).

Introduction

Introduction Absorption

Liver Metabolis

mLiver

DiseaseBlood Flow

Protein Binding

Dosage Adjustmen

t

Absorption and Liver

first-pass effect

With cirrhosis, oral drugs are distributed directly into the systemic circulation.

This means that oral drugs metabolized in the liver must be given in reduced doses.

Introduction Absorption

Liver Metabolis

mLiver

DiseaseBlood Flow

Protein Binding

Dosage Adjustmen

t

Absorption and Liver

Normal Liver Metabolism

Phase I

Microsomal Metabolism

CYP450

Nonmicrosomal

Metabolism

Hydrolysis Monoamine Oxidase

Alcohol Metabolism

Phase II

Glucuronidation Acetylation Glutathione

Introduction Absorption

Liver Metabolis

mLiver

DiseaseBlood Flow

Protein Binding

Dosage Adjustmen

t

Normal Liver Metabolism

Phase I

Microsomal Metabolism

CYP450

Nonmicrosomal

Metabolism

Hydrolysis Monoamine Oxidase

Alcohol Metabolism

Localized in SER Absolute requirement of Oxygen and

NADPH Differ in sensitivity to inhibitors and

inducing agents.

Introduction Absorption

Liver Metabolis

mLiver

DiseaseBlood Flow

Protein Binding

Dosage Adjustmen

t

Normal Liver Metabolism

Phase I

Microsomal Metabolism

CYP450

Nonmicrosomal

Metabolism

Hydrolysis Monoamine Oxidase

Alcohol Metabolism

General Inducers:AnticonvulsantsAntibiotics (Rifampin)

General Inhibitors: Acute alcohol Grapefruit juice

Introduction Absorption

Liver Metabolis

mLiver

DiseaseBlood Flow

Protein Binding

Dosage Adjustmen

t

Metabolism in Liver

Dosage should be reduced for drugs that are extensively metabolized in the liver including:

Cimetidine and Ranitidine Diazepam and Lorazepam Morphine and Meperidine (Pethidine) Phenytoin Propranolol Verapamil.

Introduction Absorption

Liver Metabolis

mLiver

DiseaseBlood Flow

Protein Binding

Dosage Adjustmen

t

Normal Liver Metabolism

Phase II

Glucuronidation

Gilbert, Crigler-Najjar

Syndrome

Acetylation

Drug induced SLE

Glutathione

Acetaminophen

hepatotoxicity

Introduction Absorption

Liver Metabolis

mLiver

DiseaseBlood Flow

Protein Binding

Dosage Adjustmen

t

Normal Liver Metabolism

Introduction Absorption

Liver Metabolis

mLiver

DiseaseBlood Flow

Protein Binding

Dosage Adjustmen

t

Liver Disease and Metabolism

The capacity of the liver to metabolize drugs depends on: Hepatic blood flow Liver enzyme activity Binding of a drug to plasma proteins.

Introduction Absorption

Liver Metabolis

mLiver

DiseaseBlood Flow

Protein Binding

Dosage Adjustmen

t

Elimination of drugs

Example

Analgesics, anxiolytics, and sedatives.

Increased cerebral effect.

Alterations in blood-brain-barrier permeability, an increased number of GABA receptors.

Encephalopathy.

Liver Blood Flow

Hepatic metabolism also depends on hepatic blood flow.

Hepatic blood flow ↓ => delivery of drug to hepatocytes ↓ => drug metabolism ↓ => drug toxicity ↑

Introduction Absorption

Liver Metabolis

mLiver

DiseaseBlood Flow

Protein Binding

Dosage Adjustmen

t

Protein Binding

Protein binding affects distribution. The impaired liver is unable to

synthesize plasma proteins (albumin) adequately.

Liver impairment causes accumulation of substances (bilirubin) that displace drugs from protein-binding sites.

Introduction Absorption

Liver Metabolis

mLiver

DiseaseBlood Flow

Protein Binding

Dosage Adjustmen

t

When protein binding ↓ => free drug ↑ => drug distribution to sites of action & elimination ↑

=> onset of drug action ↑ => duration of action ↓

When protein binding ↓ => peak blood levels and adverse effects ↑

Protein Binding

Introduction Absorption

Liver Metabolis

mLiver

DiseaseBlood Flow

Protein Binding

Dosage Adjustmen

t

Hepatic Impairment and Dosage Adjustment

For each drug case , the physician needs to assesses the degree of hepatic impairment and consider the known pharmacokinetics and pharmacodynamics of the drug.

Starting therapy with low doses and monitoring response or plasma levels provides the best opportunity for safe, efficacious treatment.

Introduction Absorption

Liver Metabolis

mLiver

DiseaseBlood Flow

Protein Binding

Dosage Adjustmen

t

Dosage calculation in liver disease:

Introduction Absorption

Liver Metabolis

mLiver

DiseaseBlood Flow

Protein Binding

Dosage Adjustmen

t

• Reduce initial dose by 50%.

• Adjust maintenance dose

High clearance

drug

• Reduce maintenance dose by 25%.

Low clearance

drug

Dosage calculation in liver disease:

Dose adaptation for patients with liver disease is more difficult than for patients with impaired renal function.

There is no endogenous marker for hepatic clearance that can be used as a guide for drug dosing

Unlike creatinine clearance for the kidney ,for liver there is no in vivo surrogate to predict the drug clearance.

Summary:

The pharmacokinetics effect of drugs in liver cirrhosis:

Absorption increase bioavailabilityDistribution decrease plasma binding

+ increase distribution Metabolism impaired Excretion impaired

References

Fabiola Delcó, et al. Dose Adjustment in Patients with Liver Disease, 2005, Drug safety; 28 (6) pp 529 – 545

Andrew sloss et al. Prescribing in Liver Disease, 2009, Australian prescriber; 32 (5)

Roger K. Verbeeck. Pharmacokinetics and Dosage Adjustment in Patients with Hepatic Dysfunction, 2008, Eur J clin pharmacol; 64 pp 1147- 1161

Roger K. Verbeeck. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol (2008) 64:1147–1161 DOI 10.1007/s00228-008-0553-z