This document discusses dosage adjustment considerations in patients with hepatic impairment. It covers hepatic drug clearance and how it is affected by factors like hepatic blood flow and extraction ratio. Drugs are classified as having high, intermediate, or low extraction ratios. The Child-Pugh score and MELD classification scheme are presented as tools to assess liver disease severity and determine appropriate dosage adjustments. Recommendations are provided for various drug types based on their extraction ratios and protein binding properties.

1. Dosage adjustment in Hepatic Failure

2. Hepatic Drug Clearance (CLH)
 The total body clearance of a drug is generally dependent
(mainly) on the hepatic and renal elimination mechanisms.
 For most drugs, hepatic metabolism is the major elimination
pathway.
 CLH is ‘the volume of blood from which the drug is
completely removed by the liver per unit time’.
 CLH is a function of…
• Hepatic blood flow (QH), and
• Hepatic extraction ratio (EH)
CLH = QH x EH
 EH depends on…
• Liver blood flow
• Intrinsic clearance of the unbound drug (Clint)
• Fraction of unbound drug in the blood (fu)

3. fu x CLint
EH = __________
QH + fu x CLint
fu x CLint
CLH = QH x _________
QH + fu x Clint
 Based on the liver’s efficiency in extracting drugs (and from
the above formulae), drugs can be classified as having …
 High Extraction Ratio (> 0.7)
 Intermediate Extraction Ratio (0.3 – 0.7)
 Low Extraction Ratio (< 0.3)

4. Oral Clearance (Clor)
 Assumptions:
• Drug is completely and exclusively eliminated by hepatic
mechanisms.
• All of the orally administered dose is absorbed by the
intestinal epithelial cells, from where it enters the portal
circulation.
Dor
Clor = _________ = fu x Clint
AUC 0 - ∞
 The Clor depends on the…
• Degree of binding to blood/plasma components
• Intrinsic Clearance

5. Dgs. w/ relatively high EH
 Oral BA can be drastically ↑ed in CLD patients; (reduce the
dosage accordingly).
 ↓ed plasma CL even after systemic admn. (i.v., i.m.,
s.c.,etc.) IF hepatic blood flow is decreased.
Dgs. w/ low EH and high PP binding (> 90%)
 CL (oral and i.v.) is determined by the intrinsic hepatic CL
and unbound drug fraction in blood or plasma.
 The intrinsic hepatic CL is reduced to an extent (based on
the liver’s functional status and specific metabolic pathways
involved).
 Generally, in CLD patients, the unbound dg. fraction is also
significantly increased, so p’cokinetic evaluations must be
based on the unbound dg. in blood / plasma conc.
 Dosage adjustment may be necessary even though total
blood/plasma conc. are within normal range. WHY????

6. Dgs. w/ low EH and low PP binding (< 90%)
 Cl (oral and i.v.) is determined by the intrinsic hepatic Cl
and unbound drug fraction in blood or plasma.
 The intrinsic hepatic Cl is reduced to an extent (based on
the liver’s functional status and specific metabolic pathways
involved).
 Fluctuations in unbound drug fraction in blood or plasma
are quite small, and will not significantly affect the blood or
plasma Cl of the dg.
 Dosage adjustment may be necessary and should aim at
maintaining the normal total (bound + unbound) plasma
conc.

7. Hepato-renal syndrome
 Advanced hepatic disease is commonly a/w impaired renal
function.
 Unexplained progressive renal failure occurring in CLD
patients in the absence of clinical, laboratory, or anatomical
evidence of other known causes of renal failure.
 ↓ed renal excretion for many dgs. which are mainly excreted
by the kidney (frusemide, bumetanide, cimetidine,
ranitidine, levetiracetam, etc.).
 Estimation of CrCl based on SCr in these patients is often
inaccurate (overestimation) due to…
• Reduced muscle mass;
• Impaired metabolism of creatine to creatinine;

8. Volume of Distribution
 ↑ed Vd of hydrophilic dgs. in CLD patients who have edema
and/or ascites;
Increase the Loading Dose if a rapid and complete effect
is required.
 Renal function should be taken into consideration as many
hydrophilic dgs. are excreted by the kidneys.
Extreme caution…
 Drugs w/ narrow therapeutic index;
 Administering any drugs to patients w/ severe liver
dysfunction (Child-Pugh classification class ‘C’)

9. Child-Pugh Score
 Used extensively in clinical practice to categorize patients
according to the severity of the liver function impairment.
 Scope:
• Tracking each individual patient’s disease course;
• Comparing patient groups;
• Offers guidance for dose adjustment.
 Incorporates 5 variables to assess the severity of liver
disease: serum bilirubin, serum albumin, PT time,
encephalopathy, and presence of ascites.
 Points: 1, 2, and 3
 The total points obtained will indicate the severity of liver
disease (mild / moderate / severe).

10. Clinical / Biochem. Indicator 1 POINT 2 POINTS 3 POINTS
Ser. Albumin (g/dL) > 3.5 2.8 – 3.5 < 2.8
Ser. Bilirubin (mg/dL) < 2 2 – 3 > 3
PT Time (secs. longer than
control)
< 4 4 – 6 > 6
Encephalopathy (grade) None 1 or 2 3 or 4
Ascites Absent Slight Moderate
TOTAL SCORE SEVERITY
5 – 6 MILD (Group ‘A’)
7 – 9 MODERATE (Group ‘B’)
10 – 15 SEVERE (Group ‘C’)

11. Calculation
• Ms. ‘R’, 57 y/o female;
• History of Presenting Illness: Admitted to the hospital
after developing an episode of ventricular arrythmia.
• PMH: Liver Cirrhosis, HTN, IHD
• Lab values:
Sr. Albumin = 3.2 g/dL
Sr. Bilirubin = 4.5 mg/dL
PT time = 8 s longer than the control
• P/E: Patient was alert without any signs of
encephalopathy. The patient has mild ascites.
 The physician wanted to initiate lidocaine therapy and
asked you to recommend an average starting dose for
this patient.

12.  Pts. w/ normal liver function can have a score of 5.
 Pts. w/ severe liver dysfunction can have a score of 15.
 Pts. w/ a score of 8-9 require 25% reduction of their
initial doses of those drugs mainly eliminated by
hepatic metabolism.
 Pts. w/ a score of ≥ 10 require 50% reduction of their
initial doses of those drugs mainly eliminated by
hepatic metabolism.
 The Child-Pugh Score serves only as a recommendation for
the starting doses of the drugs.
 After initiating the drug therapy, the pharmacological and
AEs of the drugs should be monitored, and further dosage
adjustment should be made if necessary.

13. MELD Classification Scheme
 Modification of End-stage Liver Disease
 Based on:
• Serum Bilirubin (mg/dL)
• SCr (mg/dL)
• INR of PT Time
• Underlying cause of Liver disease
 The MELD Score has accurately predicted the 3-month
mortality rate among patients awaiting liver-transplant
(Cholongitas E, et al., 2006).
MELD = 3.78 x ln[serum bilirubin] + 11.2 x ln[INR] + 9.57 x
ln[SCr] + 6.43
 MELD scores are reported as whole numbers (the answer
should be rounded off);
 Score range: 6 – 40
 If the score is closer to 40, the risk of death is higher if the
patient does not get a liver transplant. Any modification to the
scoring?????

14. THE END

15. FYI

16.  Liver diseases hepatocyte damage
reduced metabolic rate of liver
slower rate of drug metabolism
reduction in the drug first-pass effect
Higher BA
 Dosage reduction in patients w/ liver diseases may not be
necessary unless there is significant reduction in the liver’s
metabolizing ability (e.g., in liver cirrhosis)

17.  Dosage adjustment in patients w/ liver disease is harder that
for patients with kidney diseases because….
• There is no specific clinical laboratory test that can serve as
a quantitative measure for the hepatic metabolic rate.
• The different enzyme systems have different capacities for
drug metabolism (limited capacity and high capacity enzyme
systems)
 In limited capacity enzyme system, the rate of dg.
metabolism may be significantly reduced in mild or
moderate liver disease.
 In high capacity enzyme systems, a significant reduction in
liver function may be necessary before the rate of
metabolism is reduced.