1/4/2022

DRUG-DOSE ADJUSTMENT IN
PATIENTS WITH HEPATIC DISEASES

Presented by
Nermein Fawzy El Sayed
Lecturer of pharmacology and toxicology

Main liver function

kidney

metabolism

Synthesis
eg,.Plasma protein

elimination

2
Nermein Fawzy

1
 1/4/2022

• Drugs are often metabolized by one or more

enzymes located in cellular membranes in
different parts of the liver.
• Drugs and metabolites may also be excreted by
biliary secretion.

Nermein Fawzy 3

Patients at risk for impaired liver

function
• Primary liver disease
(eg, hepatitis, cirrhosis, cholestasis)
• Hepatotoxic drugs
(acetaminophen, INH, statins, methotrexate, phenytoin, aspirin and
alcohol)
• Diseases that impair blood flow to the liver
(heart failure, shock, major surgery, or trauma).
• Malnourished people or those on low- protein diets
• Presence of Clinical signs for hepatotoxicity
(nausea, vomiting, jaundice, hepatomegaly)

Nermein Fawzy 4

2
 1/4/2022

LIVER FAILURE
• Liver failure or hepatic insufficiency is the
inability of the liver to perform its normal
synthetic and metabolic function as part of
normal physiology.
• Two forms are recognized:
Acute liver failure
Chronic liver failure

Nermein Fawzy 5

Clinical laboratory tests

They measure only a limited number of liver
functions. detect liver
cell damage
 the Serum aspartate aminotransferase (AST) rather than
 Serum alanine aminotransferases (ALT) liver function

 Serum bilirubin > 4 to 5 mg/dl detect liver excretory function

used to measure biliary obstruction or interference with bile
flow.
 Albumin <2.0 g/dl
 prothrombin time (INR) detect liver Synthetic function

>1.5 times control

However, there is no single test that accurately assesses the total liver function.
6
Nermein Fawzy

3
 1/4/2022

pathophysiological changes with liver

impairment
 Hepatic disease, and in particular cirrhosis, results in numerous
pathophysiologic changes in the liver that may contribute to changing the
pharmacokinetic and pharmacodynamic behavior of many drugs.
 Changes associated with cirrhosis or responsible for PK changes of drugs
are:
 a reduction in liver blood flow
 the presence of intra- and extrahepatic portal-systemic shunting
 a capillarization of the sinusoids
 a reduction in the number and in the activity of the hepatocytes
 impaired production of albumin
 Impaired secretion of bile acids is also observed in cirrhosis
 Occurrence of a hepatorenal syndrome, which is associated with
a severe impairment of renal function.

Nermein Fawzy 7

Portal systemic
shunt

Nermein Fawzy 8

4
 1/4/2022

Hepatic disease progression will also lead to the

development of some clinical manifestations, such as:

 Esophageal varices
 Edema
 Ascites

contribute to changing
PK and PD behavior
of many drugs.

Nermein Fawzy 9

Therefore,
Hepatic disease may lead to:
 drug accumulation
A  increased bioavailability after oral administration
D  possible alteration in drug–protein binding.
M  failure to form an active or inactive metabolite.
E  Altered kidney function, which can lead to
accumulation of a drug and its metabolites even
when the liver is not primarily responsible for
elimination

Nermein Fawzy 10

5
 1/4/2022

Pharmacokinetic changes in liver

diseases
• Liver diseases without cirrhosis
usually result in mild alterations in
• Absorption drug pharmacokinetics.
• Chronic active hepatitis, and liver
• Distribution cancer are not associated with
significantly impaired hepatic
• Metabolism elimination unless cirrhosis is present
• Mainly cirrhosis and cholestasis in
• Elimination liver affect the drug PK because these
conditions may lead to situations
where dosage adjustment is
absolutely necessary to prevent
excessive drug/metabolite
accumulation and toxic effects.
Nermein Fawzy 11

Absorption
• Normally
 all drugs absorbed from the GIT (with exception of the mouth and
the lower part of the rectum) are exposed to the metabolizing
enzymes and bile excretory transport systems of the liver
before reaching the systemic circulation.
 Drugs with an intermediate to high hepatic extraction ratio will
undergo an important pre-systemic elimination or ‘first-pass
effect
• However, Chronic liver disease affect the bioavailability of orally
administered drugs mainly by reducing its presystemic hepatic
metabolism. why????? ……
⸫ cirrhosis Increases the bioavailability of drugs that
undergoes 1st pass metabolism

1st pass
metabolism Bioavailability
12
Nermein Fawzy

6
 1/4/2022

Nermein Fawzy 13

Plasma protein binding and distribution

Chronic liver diseases and cirrhosis
reduces albumin and α1-acid glycoprotein synthesis
leading to
 low levels of these important binding proteins in plasma of
patients with accumulation of endogenous compounds, such
as bilirubin and inhibiting plasma protein binding of certain
drugs
⸫the unbound fraction of the drug

 Causing ascites and increasing the distribution volume

of certain drugs in these patients
⸫ increase the Vd of water-soluble drugs in patients with ascites
possibly necessitating larger loading doses
• E.g. the β-lactam antibacterial cefodizime x3
Nermein Fawzy 14

7
 1/4/2022

Metabolism
• Conjugation reactions (phase 2) such as glucuronidation are often
considered to be affected to a lesser extent by liver cirrhosis than
CYP450-mediated reactions
• Selective regulation of activity for different CYP enzymes in the
presence of chronic liver disease, where the degree of reduction in
activity is dependent on CYP enzyme and severity of liver disease

Liver disease stage Metabolic changes

Early stage  Reduced CYP2C19
 Normal CYP1A2, CYP2D6, and CYP2E1

End stage Reduced CYP1A2, CYP2C19, CYP2D6, and CYP2E1

Consequently, the change in hepatic metabolism of a drug may be predicted

from knowing the individual drug-metabolizing enzymes involved in
the metabolism of the drug under normal circumstances and the sensitivity
of the enzymes to the disease process
Nermein Fawzy 15

Biliary excretion
• Reduced formation or secretion of bile into the duodenum will
lead to a decreased clearance of substances that are eliminated
by biliary excretion
• obstruction of the common bile duct causes accumulation of
the drugs or its metabolites that are normally excreted in the
bile (that undergoes glucuronidation)

Examples of drugs excreted in bile:

ampicillin, piperacillin, certain
cephalosporins, clindamycin, and
ciprofloxacin
There biliary excretion is impaired
in patients with obstructed biliary
tract
Nermein Fawzy 16

8
 1/4/2022

Renal excretion
• Advanced hepatic disease is commonly complicated by impaired renal
function
• The hepatorenal syndrome may be defined as unexplained
progressive renal failure occurring in patients with chronic liver disease
in the absence of clinical, laboratory, or anatomical evidence of other
known causes of renal failure
• Reduced renal excretion has been reported for a number of
drugs mainly excreted in unchanged form by the kidneys in patients
with advanced cirrhosis accompanied by impaired renal function
• such as the:
diuretics furosemide and bumetanide
 H2-receptor antagonists cimetidine and ranitidine
 antiepileptic levetiracetam

Nermein Fawzy 17

• Therefore,
Dosage adjustment in patients with liver
dysfunction is therefore essential for many
drugs to avoid excessive accumulation of the
drug, and possibly of active drug
metabolite(s), which may lead to serious
adverse reactions.

Nermein Fawzy 18

9
 1/4/2022

Dose adjustment for patients with

liver diseases
• Dose adjustment for patients with liver disease is
more difficult than for patients with impaired renal
function.
• unlike the CrCl that has been used successfully to
measure kidney function and renal clearance of
drugs for the kidney, for the liver there is no in
vivo markers to predict hepatic drug clearance.
• So, dose adaptation in patients with liver disease
can only be made based on the kinetic properties
of the drugs in patients with liver disease.
Nermein Fawzy 19

Hepatic drug clearance

• Hepatic drug clearance (CLH), defined as the volume
of blood from which drug is removed completely by
the liver per unit time, is a function of hepatic blood
flow (QH) and the hepatic extraction ratio (EH) of the
drug:
in Liver out

• CLH= QH x EH Elimina
ted

= Q x (Cin – Cout)/Cin
Cin is the conc. Of a drug in the portal vein
Cout is the hepatic outflow conc.
Nermein Fawzy 20

10
 1/4/2022

CLH= QH x EH = Q x (C in –C out)/C in

Since EH depends on:

 liver blood flow,
 the intrinsic clearance of unbound drug (CLint)
 the fraction of unbound drug in blood (fu)

𝐸= fu × Clint out
in Liver
Q+(fu × Clint)
Clint is the intrinsic hepatic clearance Elimina
ted
fu is the fraction of unbound drug to serum proteins.

the following fundamental equation for CLH has been derived:

Cl hep= 𝑄 × fu × Clint
Q+(fu × Clint) 21
Nermein Fawzy

• This equation is based on the “well-stirred”

model

The three primary determinants of hepatic drug clearance are:

 blood flow Q
 drug binding in blood Fu
 the intrinsic clearance Clint(activity of enzymes and
transporters involved in the hepatic elimination of drugs
by metabolism and biliary excretion)

The hepatic intrinsic clearance (CLint) represents the ability

of the liver to clear unbound drug from the blood when there are
no limitations of flow
Nermein Fawzy 22

11
 1/4/2022

Drug substances can be categorized according to the

efficiency of the liver in removing the substance from
the circulation as :
• Highly extracted drugs (EH>0.7)
 The hepatic clearance of highly extracted drugs is said to be
limited by liver blood flow and is relatively insensitive to
changes in binding of drug to blood components or
enzyme/transporter activity, i.e.Fu, Clint. Extraction is high
When (fu x Cli) >> Q and high intrinsic cl
Equation can be simplified to Clhep ≈ Q
in Liver out
• Low extracted drugs (EH<0.3)
“ENZYME-LIMITED”
When (fu x Cli) is << Q , Eliminated

 Equation can be simplified to Clhep ≈ (fu x Cli)

• Intermediate extraction drugs (0.3<EH<0.7)
Where the hepatic clearance of these drugs is determined by
both Q and (fu x Cli)

Nermein Fawzy 23

Hepatic extraction ratio

Drugs with low Extraction ratio Drugs with high Extraction ratio
Erythromycin Propranolol

Warfarin Verapamil

Diazepams Nitroglycerine

Tolbutamide Morphine

phenobarbitals lidocaine
Extraction is high
and high intrinsic cl

Not affected by
in Liver out
blood flow

Eliminated
Nermein Fawzy 24

12
 1/4/2022

DOSE ADJUSTMENT FOR HIGH

EXTRACTION DRUGS
• this reduction cannot be predicted accurately but a conservative
approach is to assume a 100% oral bioavailability of such drugs in
case of reduction of blood flow to the liver.

Reduced dose = normal dose × bioavailability /100

• ” Normal dose” is the starting dose in a patient without liver disease

• “bioavailability” the percentage of a drug ingested orally reaching the
systemic circulation in a healthy person.
• N.B.
Both the initial dose and maintenance dose have to be reduced

Nermein Fawzy 25

DOSE ADJUSTMENT FOR LOW EXTRACTION

DRUGS OR ENZYME LIMITED DRUGS
• Low extraction drugs undergo a low extraction during the first
passage across the liver (≤ 30%) and have therefore a
bioavailability which is ≥ 70%
• their Clhep is mainly determined by the product fu x Cli.
• Its bioavailability is not affected grossly by liver disease but their
hepatic clearance may be reduced depending on their hepatic
metabolism (reflecting Cli) and binding to albumin (fu).
• Clhep ≈ (fu x Cli)
• N.B. Maintenance dose should be reduced
• The reduction in Cli associated with liver disease appears to be
function of the Child’s Pugh score

Nermein Fawzy 26

13
 1/4/2022

Child’s Pugh score

• used to formulate drug dosing recommendations and classification

of liver disease severity in patients with liver disease. 27
Nermein Fawzy

INTERMEDIATE EXTRACTION DRUGS

DOSE ADJUSTMENT
Since bioavailability of these drugs is 40% or more, the influence of blood
flow (Q) is less pronounced as compared to “high extraction” drugs
• But in general, Clhep of these drugs is reduced.
• Also the hepatic clearance of these drugs is determined by
both
Q and (fu x Cli)
• So, treatment should be started with a lower initial dose
• But for maintenance doses it has to calculated as for low extraction
drugs
• Example
Carvedilol therapy in cirrhotic patients is 1/5 the normal dose

Nermein Fawzy 28

14
 1/4/2022

If no studies or recommendations specific to the drug

are available, it is recommended to use child’s pugh
scoring as following:

• Patients with Child class A

a maintenance dose of 50% of normal.
• patients with Child class B
a maintenance dose of 25% of normal.
• Patients with Child class C
use of drugs whose safety has been demonstrated in
clinical trials and/or whose kinetics is not affected
by liver disease or for which therapeutic drug
monitoring is available
Nermein Fawzy 29

• The most dangerous drugs in patients with liver

cirrhosis are those with a low bioavailability and
a narrow therapeutic range when administered
orally.
• For these drugs, both initial and maintenance doses
have to be reduced by 50% or more of the normal
dose, depending on the severity of liver disease,
hepatic extraction and metabolism, and toxicity of the
drug.

Nermein Fawzy 30

15
 1/4/2022

Altered pharmacodynamics in liver

disease
The most important changes in pharmacodynamics observed in cirrhosis are
those associated with:
 Patients with liver cirrhosis are more sensitive to the renal adverse
effects of nonsteroidal anti-inflammatory drugs (NSAIDs)
 Diuretics effect decrease with cirrhosis due to a reduction in both the
number of nephrons and the maximum response per nephron
 opioid analgesics Show an increased cerebral effect in cirrhotic patient
 Anxiolytics in comparison to healthy subjects
 sedatives
• Encephalopathy may be precipitated when “therapeutic” doses of these
drugs are administered to patients with cirrhosis
• Various hypotheses include:
 Alterations in blood-brain-barrier permeability
 Increased number of GABA ligands and receptors increasing its
sensitivity

Nermein Fawzy 31

References
• “Principles of Clinical Pharmacology”
textbook, Third edition
• Katzung Basic And Clinical Pharmacology,
McGraw Hill Education 13th edition

Nermein Fawzy 32

16
 1/4/2022

Thank You

Nermein Fawzy 33

17