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Sir:
I have a question about Pharmacokinetics of Lidocaine, I hope someone can
write to me and solve the problem that I encountered. Thank you very much!
Lidocaine is used for continuous extradural infusion as anaesthetic
purpose during surgery. In order to calculate the dose rate(Ko) , which
pharmacokinetic model should be chosen to calculate it ? I don't know if it
is right to use the routine equation of intravenous infusion or there is
other proper models for this case.
Some one use the extravascular steady state model to simulate the case
as follows:
Css=FXo/(vkT) (T=interval time)
=FXo*(t1/2)*1.44/(v*T)
Replaced Xo with Ko*T then
Css=FKoT(t1/2)*1.44/(v*T)=1.44FKo(t1/2)/v
when Css is known, then the Ko can be calculated from the above equation:
Ko=Css*v/(1.44F(t1/2))
Is this theory correct?
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[Three replies - db]
X-Sender: smelethil.-a-.cctr.umkc.edu
Date: Mon, 01 Jun 1998 12:37:28 -0500
To: PharmPK.at.pharm.cpb.uokhsc.edu
From: Sri Melethil
Subject: Re: PharmPK (No subject)
Mime-Version: 1.0
Dear colleague,
Lidocaine is a two compartment drug. The equations you present are based
on the one compartment model. I am not sure what exactly "extradural"
means. However, if there is no need for rapid achievement of
steady-stateof blood/plasma concentrations, then using the steady-state
equation for continuous infusion :
Cp(ss) = k0/(Vc*kel) = k0/[(Vd (beta) * beta]
should work. If you have more questions, please contact me.
Good luck
Srikumaran Melethil, Ph.D.
Professor, Pharmaceutics and Medicine
Schools of Pharmacy and Medicine
University of Missouri-Kansas City
203B Katz Hall
Kansas City, Mo 64110
816-235-1794 (fax; 816-235-5190)
---
Date: Mon, 1 Jun 1998 14:03:14 -0400 (EDT)
From: JOGARAO VS GOBBURU
To: PharmPK.-a-.pharm.cpb.uokhsc.edu
cc: Multiple recipients of PharmPK - Sent by
Subject: Re: PharmPK (No subject)
MIME-Version: 1.0
By theory: k0 = Css*CLs is correct. However, taking into consideration
Lidocaine's rapid distribution and probability of toxicity (> 2ug/mL), the
dosing regimen, practically, can be more complicated than just using the
above formula. Several dosing patterns have been studied: 1) multiple
bolus doses, (2) exponentially decreasing rate of infusion, (3)
step-infusions.
With regards,
Joga
==============================================================================
Jogarao Gobburu
Center for Drug Development Science
Room NE 405 Med-Dent Building
3900 Reservoir Road NW,
Washington, DC 20007.
Ph : 202-687-7779
Fax: 202-687-0193
E-mail:gobburuj.-at-.gunet.georgetown.edu
www.dml.georgetown.edu/cdds
===============================================================================
---
From: Olof.Borga.at.draco.se.astra.com
To: PharmPK.aaa.pharm.cpb.uokhsc.edu
Subject: Pharmacokinetics of Lidocaine
Date: Tue, 2 Jun 1998 13:49:20 +0200
Mime-Version: 1.0
Dear Shen Zancong,
There are actually two questions that should be addressed first: 1) What
is the procedure to be used in the "extradural" infusion? 2) Is your aim
to rapidly reach a plateau concentration in plasma or somewhere else?
Then to your actual question; is the theory correct? Yes it is, if your
aim is to produce a certain plateau concentration in plasma. With your
equation you will be able to calculate the infusion rate that will
produce the concentration in plasma that you want to maintain. I assume
that F in your equation is =1.0. Another way of doing the calculation,
if you don't have explicit numbers for t1/2 and V is to realize that
Ko=CLxCss.
However, as pointed out above, in the practical application of
pharmacokinetics one has to consider the purpose of the overall
procedure. Do you want to achieve an effect rapidly? Do you have to give
a loading dose, and how should that dose be calculated? Where exactly
are you going to inject your drug? Which concentration is it that you
want to keep at a steady level? Once you know the answers to these
questions, you should be able to rephrase your pharmacokinetic problem.
There are a few things to be remembered about the PK of lidocain. First,
it is typically described with a 2-compartmental model. Second, while
the rythm stabilizing effect on the heart comes within a few minutes,
other effects may develop more slowly, and will depend upon the time
needed for the drug to reach its target in the tissue./OLOF BORGA
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RE: Question about extra-dural lidocaine - appropriate model
It appears to me that the originator of this question is more
interested in the efficicay of lidocaine for regional
anesthesia. The infusion is directed in the extra-dural space
(outside the dura matter) of the thoracic, lumbar or sacral veterbrae
to acheive anaesthesia of areas innervated by the region infused.
The site of action probably involves the nerve roots as they
emerge from the dural sheath. My suspicision is that no
pharmacokinetic data exists to describe the disposition of lidocaine
from the site or infusion, and we know nothing about which model
would be appropriate. Perhaps the use of a microdialysis probe could
characterize local concentrations in the epidural space, then the
data could be examined to determine the best model to use.
If the question relates to systemic absorption, then data from the
serum could be examined to determine the best model to describe the
absorption. Although, a two compartment model is appropriate for IV
injection/infusion, it is possible that a one compartment model may
be adequate if extravascular absorption is involved. The pronounced
distribution phase would be greatly reduced in this setting.
David Nix
The University of Arizona
nix.aaa.pharmacy.arizona.edu
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It was stated (by Joga) that distribution issues and probability of
toxicity would make the application of the single infusion equation
inappropriate. As I pointed out, distribution issues come into play only
if rapid achievement of Cpss is needed. As far as toxicity is concerned,
it is not an issue. The single infusion will gradually take the patient to
the set Cp; so, as long a clinically safe concentration (2-6 ug/ml) is
selected, with no requirement of rapid achievement of the desired Cpss,
the suggested equation should work just fine.
I am familiar with the more complicated infusion procedures the author
refers to; they do not seem to be applicable to the question originally
raised.
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Assumptions: Xo = total dose
F = bioavailability
V = volume of distribution
k=elimination rate constant
T=total duration of the infusion
Then Xo/T = rate of infusion (Ko)
k*V = Clearance (CL)
It is true that Css=Ko/CL and the above equation
is correct.
> =FXo*(t1/2)*1.44/(v*T)
> Replaced Xo with Ko*T then
It is true that Xo = Ko*T
Usually F is not a part of the equation; however, there
could be loss of drug to the infusion apparatus.
Css = FXo/T * t1/2 * 1.44/V
Css = [ F*Rate of Infusion] * [t1/2 *1.44/V]
This equation would be true if [t1/2*1.44/V] = 1/ Clearance
CL = k*V k=0.693/t1/2
CL= 0.693/t1/2 *V
CL= 0.693*V/t1/2
1/CL = 1.44 * t1/2 /V
Thus, the above equation is true.
>
> Css=FKoT(t1/2)*1.44/(v*T)=1.44FKo(t1/2)/v
Css = F Xo/T * t1/2 * 1.44/V here, you have replaced Xo
with Ko*T and have rearranged the other parts. An easier
approach would be just to replace XoT with Ko. -- The
equation is true.
>
> when Css is known, then the Ko can be calculated from the above equation:
>
> Ko=Css*v/(1.44F(t1/2))
this rearrangement is OK.
The equations that you have are correct - previous comments make by
me and others were directed towards understanding how the equations
would be used, not if they were correct mathematically. I hope this
answers your question.
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