Disease State

Pharmacokinetics
• Introduction
• Administration of the same dose of
the same drug to different pts may
give different responses due to
differences in the pharmacokinetics,
which in turn may be due to
differences in weight, age, disease,
genetic factors, drug interactions, and
other physiological and pathological
conditions.
• Individualization of drug therapy is
especially important in certain
conditions as discussed below:
• - Renal or hepatic disease will
decrease the elimination or
metabolism
• - Dialysis procedures remove some
medications from the body
• - Heart failure results in low
cardiac output which decreases
blood flow to eliminating organs,
and drugs with moderate-to-high
extraction ratios are particularly
sensitive to this.
• - Obesity adds excessive adipose
tissue to the body which may
change the way drugs distribute in
the body and alter the volume of
distribution.
• - Drug interactions can inhibit or
induce drug metabolism, alter
drug protein binding, or change
blood flow to eliminating organs.
• Patients With Kidney Dysfunction
• There are many factors affect drug
pharmacokinetics in these pts.
• Fraction of Dose Excreted
Unchanged in Urine
• Drugs with larger fraction excreted
in urine affected more than
others, hence, require more
reduction in dose.
• Degree of Kidney Dysfunction
• The decrease in kidney function
results in a proportional decrease
in the rate of renal elimination of
the drug. Patients with low kidney
function require larger reduction
of their doses to achieve
therapeutic drug concentrations.
• DOSAGE ADJUSTMENT IN
PATIENTS WITH RENAL
DYSFUNCTION
• The Giusti and Hayton method
and the Tozer approach for dosage
adjustment in renal failure
patients are used which have the
following assumptions:
• Kidney dysfunction does not affect
the concentration-effect
relationship.
• The decrease in kidney function
results in a proportional decrease
in the rate of renal drug
elimination.
• The decrease in kidney function
does not affect the nonrenal drug
elimination.
• The decrease in kidney function
does not affect drug absorption or
distribution.
• Both methods require: the
average drug dose in pts with
normal kidney function, the
kidney function, and the fraction
of drug dose excreted unchanged
in urine to calculate the dose
required for pts with kidney
dysfunction.
• Determination of Kidney Function
• The kidney function is expressed
as the fraction of the normal
kidney function.
• The creatinine clearance
represents an accurate measure of
the kidney function.
• The fraction remaining of kidney
function is determined from the
ratio of the creatinine clearance in
the pt to the normal creatinine
clearance.
• KF = CrCLfailure/CrCLnormal
• The CrCL can be measured directly
from 24-hr urine collection.
• Also, mathematical expressions
can be used to estimate the CrCL
from such pt information as age,
weight, gender, and serum
creatinine.
• These methods of CrCL estimation
are empirical and are developed
statistically to predict CrCL from
pts' information.
• The CrCL estimation methods
differ in the accuracy in different
pt populations.
• An example of these CrCL
estimation methods is the
Cockroft and Gault method, as in
Equations below:
• For males:
• CrCL = (140-age)(Wt in
Kg)/72(serum Cr in mg/dl)
• For females:
• CrCL = 0.85[(140-age)(Wt in
Kg)/72(serum Cr in mg/dl)]
• Determination of the Fraction of Dose
Excreted Unchanged in Urine
• The fraction of dose excreted
unchanged in urine is determined from
the ratio of the total amount of the
drug excreted in urine and the
intravenous (IV) dose:
• Fraction (f) = Ae∞/D
• For the oral dose:
• The fraction excreted unchanged
in urine can be determined from
the ratio of the Ke to K or the CLR
to CLT
• Fraction (f) = Ke /K = CLR / CLT
• Determination of Dosage
Requirements in Patients with
Reduced Kidney Function
• The dose for pts with kidney
dysfunction can be calculated
from the following expression:
• Dosefailure = Dosenormal[f(KF-1)+1]
• Where f is the fraction of the drug
dose normally excreted
unchanged in the urine after an IV
dose in patients with normal
kidney function, and KF is the
fraction remaining of the kidney
function.
• Also, the t1/2 of the drug in pts with
renal dysfunction can be
determined from the following
relationship:
• t1/2failure = t1/2normal /[f(KF-1)+1]
• EXAMPLE
• A pt admitted to a hospital because of acute MI was started
on oral antiarrhythmic medication.
• He was given the average recommended dose for pts with
normal kidney function, which is 600 mg every 12 hr from an
oral formulation known to be rapidly and completely
absorbed.
• At steady state, the Cmax and Cmin were 40 mg/L and 10mg/L,
respectively.
• 1. Calculate mathematically the 1/2 and the Vd.
• 2. The patient suddenly developed acute renal failure, and
the KF dropped to 30%. If the CLR of this drug is 70% of the
CLT, then recommend an appropriate dose for this patient
after development of renal failure.
• 3. Calculate the Cmax and Cmin achieved from the new regimen.
• Answer
• 1. Cpss.max - Cpss.min = D/Vd
40mg/L - 10mg/L = 600mg/Vd
Vd = 600mg/L/30mg = 20L
Cpss.min = Cpss.max e-KT
10mg/L = 40mg/L e-KT
10mg/L = 40mg/L e-K12hr
Ln(10mg/L/40mg/L) = -K12hr
-1.386 = -K12hr
K = 0.1155hr-1
t1/2 = 6hr
• 2. f = CLR/CLT = 70/100 = 0.7
KF = 0.3
Dfailure = Dnormal[f(KF-1)+1]
Dfailure = 600mg/12hr[0.7(0.3-1)+1]
Dfailure = 294mg/12hr

• 3. t1/2failure = t1/2normal/[f(KF-1)+1] =

6hr/[0.7(0.31)+1] = 12.24hr
Kfailure = 0.693/12.24 = 0.0566hr-1
Cpss.max = D/Vd(1-e-KT)
Cpss.max = 294/20L(1-e-0.0566x12) = 29.8mg/L
Cpss.min = Cpss.max e-KT
Cpss.min = 29.8mg/L e-0.0566x12 = 15.1mg/L
• PATIENTS WITH LIVER DISEASES
• Liver diseases can lead to
hepatocyte damage, which results
in reduction of the metabolic rate
of the liver.
• The reduction in the hepatic drug
metabolism can lead to a slower
rate of drug metabolism and
reduction in the first-pass effect,
and higher bioavailability.
• Dosage reduction in patients with
liver diseases may not be
necessary unless there is
significant reduction in the liver's
metabolizing ability, such as in
patients with liver cirrhosis and for
the drugs that are mainly
eliminated by metabolism.
• Dosage adjustment in patients
with liver diseases is not as easy as
in kidney diseases because there is
no clinical laboratory test that can
serve as a quantitative measure
for the hepatic metabolic rate.
• Also, the different enzyme systems
have different capacities for drug
metabolism. So, for a limited-
capacity enzyme system, the rate;
of drug metabolism may be
significantly reduced with mild or
moderate liver disease, unlike a
high-capacity enzyme systems.
• These two factors make the
dosage adjustment in patients
with liver disease a difficult task.
• There are several methods used
for dosage calculations in patients
with liver diseases, including the
method dependent on the Child-
Pugh score.
• Child-Pugh score
• The liver’s metabolizing ability is
assessed in this method from the
determination of the Child-Pugh
score.
• This score is dependent on five
different laboratory tests and
clinical conditions: serum albumin,
total bilirubin, Prothrombin time,
ascites, and encephalopathy.
• Each of these parameters can take
a score from 1 (normal) to 3
(severely abnormal) see the table
below.
• The total Child-Pugh score is
calculated from the sum of the
scores for all the parameters.
• Patients with normal liver function
can have a score of 5; patients
with severe liver dysfunction can
have a score of 15.
• Patients with a score of 8-9
require 25% reduction of their
initial doses of drugs mainly
eliminated from the body by
hepatic metabolism (>60%
metabolized); patients with a
score of 10 or more require 50%
reduction.
• It is important to note that this is a
recommendation for the starting
doses of the drugs.
• After starting the drug therapy, the
pharmacological and adverse
effects of the drugs should be
monitored, and further dosage
adjustment should be made if
necessary.
• Parameters Used in the Calculation of the Child-
Pugh Score and the Breakdown of the Score for
Each Parameter.
Score
parameter
1 2 3

Serum albumin > 3.5 2.8-3.5 < 2.8

(g/dl)
Total bilirubin < 2.0 2.0-3.0 > 3.0
(mg/dl)
Prothrombin time < 4 4-6 >6
(seconds longer
than control)
Ascites Absent Mild Moderate

Encephalopathy None Moderate Severe

• EXAMPLE
• A 55-year old female was admitted to the hospital after
developing an episode of ventricular arrhythmia.
• The patient had a history of multiple medical problems,
including liver cirrhosis, hypertension, and ischemic heart
disease.
• Her laboratory values on admission were 1.1mg/dl serum
creatinine, 3.2 g/dL serum albumin, 4.5 mg/dL total
bilirubin, and a prothrombin time 8s longer than the control.
• Physical examination showed that the patient was alert
without any signs of encephalopathy, and the patient had
mild ascites.
• The physician wanted to start the patient on lidocaine and
asked you to recommend an average starting dose of
lidocaine.
• Answer
• Lidocaine is an antiarrhythmic drug that is
completely metabolized. First calculate the Child-
Pugh score for this patient to see if dosage
reduction is necessary. For calculation of the Child-
Pugh score refer to the table above.
• serum albumin 3.2mg/dL score = 2
• total bilirubin 4.5 mg/dL score = 3
• prothrombin time 8s > than cont score = 3
• Ascites mild score = 2
• Encephalopathy absent score = 1
total Child-Pugh score = 11
• Based on the Child-Pugh score, the
starting dose of lidocaine for this
patient should be 50% of the
average recommended dose. And
it should be noted that the
lidocaine dose can be adjusted
after the start of therapy
according to its therapeutic and
adverse effects.