# PharmPK Discussion - Pharmacokinetics of Lidocaine

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• On 1 Jun 1998 at 10:54:19, shen zancong (zcshen.-a-.public.fhnet.cn.net) sent the message
`Sir: I have a question about Pharmacokinetics of Lidocaine, I hope someone canwrite to me and solve the problem that I encountered. Thank you very much!  Lidocaine is used for continuous extradural infusion as anaestheticpurpose during surgery. In order to calculate the dose rate(Ko) , whichpharmacokinetic model should be chosen to calculate it ? I don't know if itis right to use the routine equation of intravenous infusion or there isother proper models for this case.     Some one use the extravascular steady state model to simulate the caseas 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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• On 2 Jun 1998 at 09:38:53, David_Bourne (david.-at-.pharm.cpb.uokhsc.edu) sent the message
`[Three replies - db]X-Sender: smelethil.-a-.cctr.umkc.eduDate: Mon, 01 Jun 1998 12:37:28 -0500To: PharmPK.at.pharm.cpb.uokhsc.eduFrom: Sri Melethil Subject: Re: PharmPK (No subject)Mime-Version: 1.0Dear colleague,Lidocaine is a two compartment drug.   The equations you present are basedon the one compartment model.  I am not sure what  exactly "extradural"means.  However, if there is no need for rapid achievement  ofsteady-stateof blood/plasma concentrations, then using the steady-stateequation for continuous infusion :Cp(ss) = k0/(Vc*kel) = k0/[(Vd (beta) * beta]should work.   If you have more questions, please contact me.Good luckSrikumaran  Melethil, Ph.D.Professor, Pharmaceutics and MedicineSchools of Pharmacy and MedicineUniversity of Missouri-Kansas City203B Katz HallKansas City, Mo 64110816-235-1794 (fax; 816-235-5190)---Date: Mon, 1 Jun 1998 14:03:14 -0400 (EDT)From: JOGARAO VS GOBBURU To: PharmPK.-a-.pharm.cpb.uokhsc.educc: Multiple recipients of PharmPK - Sent by Subject: Re: PharmPK (No subject)MIME-Version: 1.0By theory: k0 = Css*CLs is correct. However, taking into considerationLidocaine's rapid distribution and probability of toxicity (> 2ug/mL), thedosing regimen, practically, can be more complicated than just using theabove formula. Several dosing patterns have been studied: 1) multiplebolus doses, (2) exponentially decreasing rate of infusion, (3)step-infusions.With regards,  Joga==============================================================================Jogarao GobburuCenter for Drug Development ScienceRoom NE 405 Med-Dent Building3900 Reservoir Road NW,Washington, DC 20007.Ph : 202-687-7779Fax: 202-687-0193E-mail:gobburuj.-at-.gunet.georgetown.edu                                              www.dml.georgetown.edu/cdds===============================================================================---From: Olof.Borga.at.draco.se.astra.comTo: PharmPK.aaa.pharm.cpb.uokhsc.eduSubject: Pharmacokinetics of LidocaineDate: Tue, 2 Jun 1998 13:49:20 +0200Mime-Version: 1.0Dear Shen Zancong,There are actually two questions that should be addressed first: 1) Whatis the procedure to be used in the "extradural" infusion? 2) Is your aimto rapidly reach a plateau concentration in plasma or somewhere else?Then to your actual question; is the theory correct? Yes it is, if youraim is to produce a certain plateau concentration in plasma.  With yourequation you will be able to calculate the infusion rate that willproduce the concentration in plasma that you want to maintain. I assumethat 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 thatKo=CLxCss.However, as pointed out above, in the practical application ofpharmacokinetics one has to consider the purpose of the overallprocedure. Do you want to achieve an effect rapidly? Do you have to givea loading dose, and how should that dose be calculated? Where exactlyare you going to inject your drug? Which concentration is it that youwant to keep at a steady level? Once you know the answers to thesequestions, 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, whilethe rythm stabilizing effect on the heart comes within a few minutes,other effects may develop more slowly, and will depend upon the timeneeded for the drug to reach its target in the tissue./OLOF BORGA`
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• On 3 Jun 1998 at 10:07:04, "David Nix" (nix.at.Pharmacy.Arizona.EDU) sent the message
`RE: Question about extra-dural lidocaine - appropriate modelIt appears to me that the originator of this question is moreinterested in the efficicay of lidocaine for regionalanesthesia.  The infusion is directed in the extra-dural space(outside the dura matter) of the thoracic, lumbar or sacral veterbraeto acheive anaesthesia of areas innervated by the region infused.The site of action probably involves the nerve roots as theyemerge from the dural sheath.  My suspicision is that nopharmacokinetic data exists to describe the disposition of lidocainefrom the site or infusion, and we know nothing about which modelwould be appropriate.  Perhaps the use of a microdialysis probe couldcharacterize local concentrations in the epidural space, then thedata could be examined to determine the best model to use.If the question relates to systemic absorption, then data from theserum could be examined to determine the best model to describe theabsorption.  Although, a two compartment model is appropriate for IVinjection/infusion, it is possible that a one compartment model maybe adequate if extravascular absorption is involved.  The pronounceddistribution phase would be greatly reduced in this setting.David NixThe University of Arizonanix.aaa.pharmacy.arizona.edu`
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• On 3 Jun 1998 at 10:07:35, Sri Melethil (smelethil.-a-.cctr.umkc.edu) sent the message
`It was stated (by Joga)  that  distribution issues and probability oftoxicity would make the application of the single infusion equationinappropriate.  As I pointed out, distribution issues come into play onlyif 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 tothe set Cp; so, as long a clinically safe concentration (2-6 ug/ml) isselected, 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 authorrefers to; they do not seem to be applicable to the question originallyraised.`
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• On 10 Jun 1998 at 14:06:11, "David Nix" (nix.aaa.Pharmacy.Arizona.EDU) sent the message
`        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 byme and others were directed towards understanding how the equationswould be used, not if they were correct mathematically.  I hope thisanswers your question.`
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