- On 1 Jun 1998 at 10:54:19, shen zancong (zcshen.-a-.public.fhnet.cn.net) sent the message

Back to the Top

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? - On 2 Jun 1998 at 09:38:53, David_Bourne (david.-at-.pharm.cpb.uokhsc.edu) sent the message

Back to the Top

[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 - On 3 Jun 1998 at 10:07:04, "David Nix" (nix.at.Pharmacy.Arizona.EDU) sent the message

Back to the Top

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 - On 3 Jun 1998 at 10:07:35, Sri Melethil (smelethil.-a-.cctr.umkc.edu) sent the message

Back to the Top

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. - On 10 Jun 1998 at 14:06:11, "David Nix" (nix.aaa.Pharmacy.Arizona.EDU) sent the message

Back to the Top

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.

Want to post a follow-up message on this topic? If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "Pharmacokinetics of Lidocaine" as the subject

PharmPK Discussion List Archive Index page

Copyright 1995-2010 David W. A. Bourne (david@boomer.org)