Anesth Pain Med 2015; 10: 235-244 http://dx.doi.org/10.17085/apm.2015.10.4.235 종설 약동학과약역학원리에기초하여정맥마취제의용량요법을계획하는방법 제주대학교의학전문대학원마취통증의학교실 박종국 How to design intravenous anesthetic dose regimens based on pharmacokinetics and pharmacodynamics principles Jong Cook Park Department of Anesthesiology and Pain Medicine, Jeju National University School of Medicine, Jeju, Korea Pharmacokinetics is the study of the rate and degree of drug transport to various tissues in the human body. Pharmacokinetic parameters summarize drug kinetics and ideally predict a clinical situation. A single kinetic profile may be summarized by peak concentration, peak time, half-life and area under the curve. Dosage regimens are designed to confer the maximum desired effects for the required time period with minimal toxicity. Target-controlled infusions use pharmacokinetic models to titrate intravenous anesthetic administration to achieve a desired drug concentration. Context-sensitive half time is used to predict the clinical time course, rather than terminal half-life. It is important that anesthesiologists understand the basic pharmacological principles and apply them in their daily clinical practice. This review discusses the ways in which anesthesiologists can design a patient-specific dosage regimen of intravenous anesthetics by utilizing basic concepts of pharmacokinetics and pharmacodynamics using pharmacokinetic simulations. (Anesth Pain Med 2015; 10: 235-244) Key Words: Intravenous anesthetics, Pharmacodynamics, Pharmacokinetic parameter, Pharmacokinetics, Target controlled infusion. Received: August 7, 2015. Revised: 1st, September 30, 2015; 2nd, October 5, 2015. Accepted: October 6, 2015. Corresponding author: Jong Cook Park, M.D., Ph.D., Department of Anesthesiology and Pain Medicine, Jeju National University School of Medicine, Aran 13-gil, Jeju 63241, Korea. Tel: 82-64-717-2028, Fax: 82-64-750-1166, E-mail: pjcook@jejunu.ac.kr This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 서론약물을투여할때기대되는약리작용이외의반응은모두부작용으로간주하며바람직하지않은것을약물부작용 (adverse drug reaction) 이라고한다. 약물의부작용은원하지않게혈장농도가증가하거나약물에대한과민반응 (hypersensitivity reaction) 으로발생한다. 약물-질병및약물-약물의상호작용은혈장농도를증가시키는흔한원인이며과민반응은드물지만발생을예측하기어렵다. 정맥마취제와근이완제는작용발현시간이빠르고안전역이좁기때문에이러한약물을사용하기위해서약리학적지식과많은경험을요구한다. Propofol과 [1] remifentanil 같은정맥마취제는생명을위협하는약물반응을나타내므로전문적인수련을받은의사에의해서투여되어야한다고 [2] 자격을명시하고있다. 정맥마취제가비전문가에의해서투여될때의식소실, 호흡억제, 혹은심혈관계부작용이발생하여환자가사망할수있다 [3]. 또한수술중각성 (intraoperative awareness) 은부적절한마취용량에의해서발생하며환자에게심각한고통을줄수있다 [4,5]. 약동학 (pharmacokinetics) 과약역학 (pharmacodynamics) 은환자에게가장적합한약물의용량요법 (dosage regimen) 을결정하여환자의안전성을높일수있다. 목표농도조절주입 (target-controlled infusion, TCI) 은약물투여방법중가장발전된기술이며컴퓨터프로그램은정맥마취제의 TCI를모의 (simulation) 할수있다. 본논문은약동학및약역학의기본개념을설명하고정맥마취제와근이완제의용량요법을모의하여환자의안전성을향상시키고자한다. 약동학의원리약동학은약물의흡수 (absorption) 와배치 (disposition) 과정을연구하는학문분야다. 일회정맥 (intravenous, IV) 주사후약물은분포 (distribution) 와소실 (elimination) 에의해서이동하며간은약물을대사 (metabolism) 하고신장은약물을배설 (excretion) 한다. 약동학모수 (pharmacokinetic parameter) 는약 235
236 Anesth Pain Med Vol. 10, No. 4, 2015 물의이동을설명하는대푯값이고혈장농도를분석하여추정된다 [6]. 약동학의근본적인원리는약물의소실과정이일차속도 (first-order rate) 이고중심구획 (central compartment) 에서일어난다는것이다 [7]. 투여용량 (dose, D) 에따라서혈장농도나소실양은비례하지만약물의반감기 (half-life, t 1/2) 등은변하지않는다. 이것을선형약동학 (linear pharmacokinetics) 이라고부른다. 예를들어, propofol 70 mg을정맥주사하여혈장농도가 2.5 g/ml일때동일한조건에서 propofol 140 mg을정맥주사하면혈장농도가 5 g/ml라고예측할수있다 [8]. 비구획분석 (non-compartmental analysis) 은모형을사용하지않고약동학모수를추정하는방법이다 [9,10]. 시간-농도곡선에서최대혈장농도 (peak plasma concentration, C max), 최대혈장농도도달시간 (peak time, T max), 반감기및곡선하면적 (area under the curve, AUC) 을측정하고 [11] 평균체류시간 (mean residence time, MRT), 분포용적 (volume of distribution, V), 청소율 (clearance, Cl) 및생체이용율 (bioavailability, F) 과같은약동학모수를구할수있다 [10,11]. 구획분석 (compartmental analysis) 은모형을사용하여약동학모수를추정한다. 모형은신체의구조와기능을설명하며두가지모형이있다. 구획모형 (compartment model) 은복잡한장기나조직을구획과연결선으로단순화한다 [10]. 일구획모형 (one-compartment model) 은혈중농도에의해서신체를하나의구획으로설정하며정맥주사후에약물이전신으로빠르게분포한다고가정한다 (Fig. 1A). 이구획모형 (twocompartment model) 은신체를중심구획과말초구획 (peripheral compartment) 으로구분한다. 삼구획모형 (three-compartment model) 은신체를중심구획, 빠른말초구획 (rapid peripheral compartment) 및느린말초구획 (slow peripheral compartment) 으로구분한다. 또한생리학적모형 (physiological model) 은신체의생리적또는화학적지표를사용하여약물의이동을분석한다 [12](Fig. 1B). 따라서이모형은생리적요인을반영하고동물실험의결과를사람에게적용하고조직이나장기의구획을다양하게세분할수있다 [13]. 약동학모수와상호관계 Fig. 1. (A) One-compartment model; scheme for kinetic model. (B) Physiological model; scheme of a permeability rate-limited, two-compartment model. k 0; infusion rate, k 10 or ; elimination rate constant, Q; blood perfusion flow rate, C Bi and C Bo; blood concentration inflow and outflow. 약동학모수는측정방법에따라서몇가지지표를갖는다. 이들지표는서로연결되어있어일정한변환식을사용하면다른약동학모수로전환될수있다 [14]. 일구획모형의혈장농도는 C(t) 로표시하며등식은다음과같다 [11]. 등식 (1) Fig. 2. Evans blue (EB) in one-compartment model is a dye to determine plasma volume. EB of 17.5 mg is administered by i.v. injection. (A) Time-concentration curve and compartment model. (B) Y-axis is natural log scale. The arrow is half-life. C(0): plasma concentration at time 0, C(t): plasma concentration, AUC: area under the curve, t 1/2: half-life, X: dose.
박종국 :Design of dosage regimen 237 여기서 는소실속도상수 (elimination rate constant) 이며 k 10 로표시하기도한다. X와 V는각각약용량과분포용적이다. 영시간의혈장농도 C(0) 는 X/V다. 곡선하면적 AUC는혈장농도 C(t) 를시간영에서무한대까지적분한값이며다음등식과같다 [15]. 등식 (2) 반감기 t 1/2 는 C(t 1) C(t 2) 인관계인두시점의시간차 t 2 t 1 을말한다. 이관계식의양변에자연로그를취하면 log e2 = (t 2 t 1) 이고 log e2 = 0.693이므로반감기는다음등식과같다. 등식 (3) Fig. 2는 Evans blue의 [15] 혈장농도와약동학모수를모의한결과다. 구획이 n인다구획모형일때중심구획의혈장농도는 C 1(t) 로표시하며약동학모수는다음과같다. 등식 (4) 등식 (5) 등식 (6) 여기서단위배치함수 (unit disposition function, UDF) 는혈장농도 C 1(t) 를약용량 X로나눈것이다. A i 와 i 는단위배치함수의계수 (coefficient) 와지수 (exponent) 다. 다구획의반감기는말기반감기 (terminal half life, terminal t 1/2) 로부른다. Fig. 3은 pancuronium과 [14] fentanyl의 [16] 혈장농도와약동학모수를모의한결과다. Table 1은정맥마취제의 [17-23] 기본적인약동학모수를보여준다. Fig. 3. Multicompartment models. (A) and (B) are two-compartment model of pancuronium with 4 mg IV administration. (C) and (D) are three-compartment model of fentanyl with 150 g IV administration. (A) C1(t) and C2(t) are plasma concentration and tissue concentration. (C) C1(t) is plasma concentration, C2(t) and C3(t) are concentrations of peripheral compartments. The arrows are durations of terminal half-life. C1(0): plasma concentration at time 0, AUC: area under the curve, terminal t 1/2: terminal half-life, X: dose.
238 Anesth Pain Med Vol. 10, No. 4, 2015 Table 1. Volume of Distribution, Clearance and Terminal Half-life for Commonly Used Intravenous Anesthetic Drugs Drug V1 (L) Vss (L/kg) Varea (L) Cl (ml/day/kg) Terminal half-life (day) Fentanyl Sufentanil Remifentanil Alfentanil Morphine Midazolam Thiopental Propofol 6.8 16.6 4.7 8.9 17.5 33 5.5 16.0 4.2 7.0 0.3 0.5 4.0 6.6 2.6 3.6 379 1,420 184 51 409 911 231 792 20.2 32.1 89.3 12.7 56.3 13.0 7.7 67.8 0.32 0.76 0.04 0.07 0.13 1.21 0.52 0.20 V1: central volume of distribution, Vss: steady state volume of distribution, Varea: terminal volume of distribution, Cl: clearance. Fig. 4. Volume of distribution is a time-dependent variable starting from a central volume V1 until it reaches a V area. (A) and (B) are volume and mass of drug amount for pancuronium. (C) and (D) are volume and mass of drug amount for fentanyl. During the distribution phase, the decrease in amount of plasma drug X1(t) is mainly owing to the drug partition between plasma and tissue, and rather than irreversible drug elimination. During the terminal phase, the decrease in amount of plasma drug is only due to irreversible drug elimination. V area: terminal volume of distribution, X2(t) and X3(t): amounts of peripheral compartment drug, V2 and V3: volumes of peripheral compartment.
박종국 :Design of dosage regimen 239 분포용적 약용량을정맥주사할때약물은초기에는혈액에분포하지만시간이지남에따라서조직에도분포한다. 약물의분포용적은약물이분포하는체액의용적을말한다. 이때혈장의약물분포는조직과평형상태며조직의약물분포는혈장의약물분포처럼행동한다고가정한다. 시간 t에서분포용적은다음등식과같다 [15,24]. 등식 (7) 여기서 X(t) 는시간 t에서체내약용량이고 C(t) 는혈장농도다. 따라서분포용적 V(t) 는시간 t에의존하는종속변수이다. 다구획모형의분포용적은각구획의약용량을종합하고중심구획의혈장농도 C 1(t) 로나눈다 (Fig. 4). 분포용적은약용량을결정하는중요한지표이며시간이나측정하는목적에따라중심용적 (volume of central compartment, V 1), 말기분포용적 (terminal volume of distribution, V area), 항정상태분포용적 (steady-state volume of distribution, V ss) 및최대약효분포용적 (volume of distribution at time of peak effect, V(t pe)) 으로구분할수있다. 1. 중심용적 Evans blue는혈장에만분포하는일구획모형이며. 그것의분포용적은혈장용적에해당한다 [15]. 중심용적 V 1 은약용량 X를정맥주사후측정한혈장농도 C(0) 에서다음과같이구할수있다 (Fig. 4). 등식 (8) 2. 말기분포용적 일회정맥주사후에약물은분포와소실로감소한다. 혈장농도는분포기 (distribution phase) 동안에중심구획과말초구획사이의분포와소실로빠르게감소하고말기 (terminal or post-distribution phase) 동안에는단지약물의소실만으로감소한다. 말기는가성평형상태 (pseudo-equilibrium state) 에있고이때의분포용적을말기분포용적이라고하며 V area 로표시한다 [15]. 등식 (9) Fig. 4에서 pancuronium과 [14] fentanyl의 [16] 분포용적이초기에중심용적에서말기분포용적으로증가하는것을보여준다. 3. 항정상태분포용적 혈장농도가어떤수준으로일정하게유지되고약물이평형상태로분포할때이것을항정상태 (steady-state, ss) 라고부른다. 항정상태혈장농도 (steady state plasma concentration, C ss) 에도달하려면약물의투여기간은충분히길고약물의투여속도가약물의소실속도와같아야한다. 항정상태에서약용량 X는외견상변동이없다. 항정상태분포용적 V ss 는다음등식으로나타낼수있다. 등식 (10) 다구획모형에서항정상태분포용적은중심용적 V 1 과미세속도상수 (micro-rate constant, or k 1j or k j1) 에의존하며다음등식과같다 [15,25]. 등식 (11) 예를들어, 어떤모의환자 (40세/ 남자, 70 kg/170 cm) 에서 pancuronium과 fentanyl의항정상태분포용적은각각 44 L와 294 L다 (Fig. 3). 약용량 X를투여간격 (dosing interval, ) 으로반복정맥주사하면혈장농도는항정상태에서일정한범위를변동한다. 이때혈장농도는정맥주사전에가장낮고 (C min) 정맥주사후에가장높다 (C max). 이런투여방법에서항정상태분포용적은다음등식과같다 [15]. 등식 (12) 생리적학인모형에서분포용적은혈장의용적 V P, 조직의용적 V T 및조직-혈장간분배계수 (tissue-plasma partition coefficient, K P) 를사용하여다음과같이나타낼수있다 [25]. 등식 (13) 여기서 f u,t 는조직중비결합형분율과 f u,p 는혈장중비결합형분율이며, K p f u,p/f u,t 다. 항정상태에서혈장의용적은조직의용적에비해서작으므로생략한다. 조직의용적은약 1 L/kg 이므로 V ss = K p 다 [15]. 예를들어, 어떤약물의항정상태분포용적이 4.2 L/kg이면분배계수는 4.2이다. 4. 최대약효분포용적 마취제는수용체와작용할때약효가나타난다. 약물의수용체가있는가상의구획을효과처 (effect site) 라고부른다 [14,26]. 예를들어, 근이완제의효과처는근육조직이며아편유사제의효과처는뇌이다. 최대약효시간 (time to peak
240 Anesth Pain Med Vol. 10, No. 4, 2015 effect, t pe) 의혈장농도 C 1(t pe) 는효과처와평형상태에도달한다. 따라서최대약효분포용적 V(t pe) 는다음등식과같다 [27]. 청소율 등식 (14) 청소율은약물을혈액으로부터제거하는능력을나타내는상수다. 이것은어떤시간동안약용량 X를완전히제거하는데필요한혈액용적 AUC이며다음등식과같다 [11,15]. 등식 (15) 항정상태혈장농도 C ss 를일정하게유지하려면약물의투여속도 X/가약물의소실속도 Cl C ss 와같아야하므로항정상태의청소율은다음등식과같다. 등식 (16) 생리학적모형에서약물의소실은신장 (renal, R) 에서약물의배설, 간 (hepatic, H) 에서약물의대사및담즙 (biliary, B) 배설로일어난다. 전신청소율 (systemic clearance, Cl T) 은각청소율의합이며다음등식과같다 [28]. 등식 (17) 여기서신장청소율 (renal clearance, Cl R) 은전신청소율중대사과정을거치지않고소변으로배설되는청소율을말하며혈액중비결합분율 f u,b 와사구체여과율 (glomerular filtration rate, GFR) 의곱으로계산할수있다. 간청소율 (hepatic clearance, Cl H) 은간혈류속도 Q H 와간추출률 (hepatic extraction ratio, E) 에의해서결정되며다음등식과같다 [28]. 등식 (18) 여기서약물의고유청소율 (intrinsic clearance, Cl int) 은간세포안에서비결합약물을대사나담즙배설로제거할수있는능력을말한다. 이것은약물의화학적특성에의존하므로각약물마다다르다. 약물의간청소율은 f u,b Cl int 와 Q H 의상대적인크기에의해서결정된다 [28]. 예를들어, f u,b Cl int 이 Q H 보다큰약물은 Q H 이고 f u,b Cl int 이 Q H 보다작은약물은 f u,b Cl int 이다. 어떤약물의이동은약용량과비례하여증가하다가그과정이포화되면약용량의증가에도불구하고소실과정이똑같은영차속도 (zero-order rate) 를갖는다. 이러한약물은 Michaelis-Menten 약동학모형을따르며비선형약동학 (nonlinear pharmacokinetics) 에속한다. 약물의소실속도 v는다음등식과같다 [25]. 등식 (19) 여기서 v max 는최대소실속도, K M 은 Michaelis-Menten 상수다. 임상에서혈장농도는 K M 에비교하여매우낮기때문에생략할수있다. 여기에속하는약물은 phenytoin, aspirin, gabapentin 등이있다. 생체이용률 마취통증의학은정맥주사, 흡입투여및척수강내 (intrathecal) 주사를많이이용한다. 다른투여경로 (route of administration, ROA) 는경구 (per oral, PO) 투여, 근육내주사, 피하주사, 구강흡수 (buccal or sublingual), 직장 (rectal) 흡수, 경피 (transdermal) 흡수, 점막흡수및국소투여 (topical) 등이있다. 정맥외 (extravascular, EV) 투여는흡수처 (absorption site) 로부터약물의이동을요구한다. 이때약물의흡수는흡수처의생리적인특성과약물의제형 (formulation) 등으로결정되며흡수속도상수 (absorption rate constant, k a) 로나타낸다. 정맥외투여에의한약물의생체이용율 F는투여량 D 중전신순환에도달한약용량 X의비율로다음등식과같다 [11]. 등식 (20) 여기서 s는약물의염형태보정인자 (salt form correction factor) 다. 정맥주사와비교하여경구투여는흡수구획에서약물의흡수, 장의통과및간의통과때문에약물의흡수가제한된다. 약물의경구투여생체이용율 F PO 대정맥주사생체이용율 F IV 의비는다음등식과같다 [11]. 등식 (21) 여기서 F a 는흡수구획에서흡수분율, F g 는장의통과분율, F h 는간의통과분율이다. F h 는간이추출한분율 (extraction ratio, E) 의나머지인 1 E이며초회통과효과 (first pass effect) 라고부른다. 생체상모형 (biophase model) 약물의반응은혈장농도보다늦게나타난다. 생체상모형은혈장농도-반응사이의이력 (hysteresis) 현상을설명한다 [14,26,29]. Sheiner와 Stanski 등은 [14,26] 이구획모형의중심구획에효과처구획 (effect site compartment) 을추가하고효과처평형속도상수 (effect site equilibration rate constant, k e0) 가
박종국 :Design of dosage regimen 241 d-tubocurarine의약효를지연시킨다고하였다. 효과처구획의용적은거의없고중심구획과약물의이동은무시할수준이라고가정할때효과처농도 (effect site concentration, C e(t)) 는다음등식과같다 [30]. 등식 (22) 약물의효과처평형속도상수가알려져있을때최대약효시간 t pe 의추정은두가지방법을사용한다 [30]. 먼저, 반복적인시행착오학습을사용하여효과처농도가가장높은시간이최대약효시간이다 [31]. 다른방법은최대약효시간에서효과처농도의증감율이영이므로효과처농도의도함수 C e (t) 가영인시간이최대약효시간이며다음등식과같다. 등식 (23) 따라서최대약효시간을등식 (22) 에대입하면최대약효효과처농도 C e(t pe) 를구할수있다. 위와반대로임상에서측정한최대약효시간 t pe 에서효과처평형속도상수 k e0 를다음방법으로추정할수있다. 측정된최대약효시간에서혈장농도와효과처농도가평형이므로두농도차의제곱이가장적은효과처평형속도상수 k e0 를반복적시행착오학습으로구하며다음등식과같다. 등식 (24) Table 2는동일한대상 (40세/ 남자, 70 kg/170 cm) 에게아편유사제를 [17-19,32] 투여할때뇌농도 3 ng/ml에필요한약용량, 최대약효시간및최대약효분포용적을보여준다. 용량요법 (dosage regimen) 용량요법이란약물의투여방법을결정하는것을말하며약물의제형 (formulation), 투여경로, 투여용량 (dose, D), 투여간격및투여기간을포함한다. 용량요법에서중요한약동학모수는분포용적, 반감기및청소율이다 [11]. 1. 투여용량, 투여간격및약물의축적투여용량은투여목적에따라서부하용량 (loading dose, D L) 과유지용량 (maintenance dose, D M) 으로구분할수있다. 부하용량은정맥주사한후일정시간에항정상태혈중농도를얻을수있는약용량을말하며약물의분포용적에의존한다. 유지용량은항정상태혈중농도를유지하기위해서투여간격마다추가되는약용량을말하며약물의청소율에의존한다. 약용량은목표농도 (target concentration, C T) 와약물의분포용적의곱으로구할수있다 [33]. 이때분포용적은약물의 Table 2. Comparisons of Opioids' Effect Site Equilibrium Rate Constant, Volume of Distribution Time to Peak Effect, Dose and Time to Peak Effect for Targeting Effect Site Concentration of 3 ng/ml k e0 (/min) V(t pe) (L)* Dose (g) Time to peak effect (min) Remifentanil Alfentanil Fentanyl Sufentanil 0.62 16.6 49.7 1.4 0.77 11.7 35.1 2.6 0.147 50.0 150.0 3.2 0.227 59.3 177.8 3.9 k e0: effect site equilibrium rate constant, V(t pe): volume of distribution time to peak effect. *The subject for V(t pe) is a 40 year old man with 70 kg and 170 cm. 작용부위에따라서다르다 [34]. 약물의작용부위가말초구획이면분포용적은항정상태분포용적이며약물의작용부위가효과처구획이면분포용적은최대효과분포용적이다. 예를들어, 최대약효분포용적이 50 L인환자에게원하는뇌의약물농도가 3 ng/ml일때 fentanyl의약용량은 150 g이다. fentanyl의효과처평형속도상수가 0.147/min 이면 [16] 반복적시행착오학습에의해서최대약효시간은 3.1분이다. 부하용량 D L, 유지용량 D M 및투여간격 의관계식은다음과같다 [28,34]. 등식 (25) 여기서약물의축적 (accumulation) 은유지용량과투여간격에의존한다. 예를들어, 투여간격이그약물의반감기인 (log e2)/일때위등식은 D L = D M 2이다. 따라서유지용량과더불어투여간격은약물의축적을조절할수있다. 반감기는항정상태에도달하는시간과부하용량의필요성을예측할수있다 [34]. Digoxin은치료역이좁아서부하량을 3 5회로나누어투여하며 aminophylline은치명적인독성효과때문에지속정맥주입 (continuous intravenous infusion) 한다. 약물의투여경로가정맥외이고체내에필요한약용량이 X일때등식 (20) 에따라서투여용량 D는 X/(F s) 다. 진통제와같은경구약제의투여용량 D는등식 (21) 에의해서 X/(F a F g F h s) 다. 경구약제의투여용량이 D이고흡수처속도상수가일차속도상수 k a 일때혈장농도 C 1(t) 는다음등식과같다 [34]. 등식 (26) 여기서위등식은약제의정맥주사생체이용율을 1 이라고가정하며약물의최대혈장농도 C max 와최대혈장농도도달시간 T max 를추정하는데사용된다.
242 Anesth Pain Med Vol. 10, No. 4, 2015 Fig. 5. Plasma concentration versus time before and after cessation of infusion. Drugs are administrated by an intravenous infusion when the infusion is stopped at ten times duration of half-life. (A) Evans blue. (B) Pancuronium. (C) Fentanyl. The plasma concentration C(t) or C1(t) increases slowly under a fixed rate infusion, constant concentration is taken four to five times the terminal half-life of drugs to reach steady state. Note that the effect site concentration Ce(t) (dotted black line) is parallel with plasma concentration C1(t) (see text for details). 2. 지속정맥주입 일구획모형에서약물의정맥주입속도가영차속도상수 k 0 이고소실속도가일차속도상수 일때혈장농도 C(t) 는다음과같다 [35] (Fig. 1A). 등식 (27) 여기서투여시간이증가하면항정상태혈장농도는 k 0/(V ) k 0/Cl가되며항정상태에도달하는시간은정맥주입속도 k 0 에관계없이일정하다. 예를들어, Evans blue을지속정맥주입할때반감기 (7.7시간) 동안혈장농도는 100/2인 50% 에도달한다. 두배의반감기동안혈장농도는 100/2 + 50/2인 75% 에, 세배의반감기동안 100/2 + 50/2 + 25/2 인 87.5% 에, 네배일때 93.7% 에, 반감기의일곱배일때 99% 에도달한다 (Fig. 5A). 다구획모형에서말기반감기는지속정맥주입하는동안혈장농도의상승과지속정맥주입후혈장농도의하강에필요 Fig. 6. The target concentration is set to 3 ng/ml at 10 min. The infusion pump delivers a rapid infusion rate to reach the target concentration and then gradually decreases the infusion rate to maintain a constant concentration. The solid black line is plasma concentration C1(t). The dotted black line is effect site concentration Ce(t). The gray vertical lines represent the infusion rate calculated by the computer to achieve and then to maintain the target concentration.
박종국 :Design of dosage regimen 243 한시간을예측하지못한다 [36]. Pancuronium을지속정맥주입할때말기반감기 (1.6시간) 동안혈장농도는 53% 에도달한다. 두배일때 77%, 세배일때 88%, 네배일때 94%, 일곱배일때 99% 에도달한다 (Fig. 5B). Fentanyl을지속정맥주입할때말기반감기 (7.8시간) 동안혈장농도는 61% 에도달한다. 두배일때 81%, 세배일때 90%, 네배일때 95%, 일곱배일때 99% 에도달한다 (Fig. 5C). 지속정맥주입을중단한후에혈장농도는빠르게감소하는데지속정맥주입후혈장농도는상승곡선의상하대칭이동한모습과같다 (Fig. 6). 지속정맥주입기간과정맥주입후혈장농도감소시간사이의관계는상황민감성반감기 (context-sensitive half-time) 로설명한다 [37]. 지속정맥주입의효과처농도는혈장농도와평행상태가되며일회정맥주사의효과처농도와다르다 (Figs. 5B and 5C). 목표농도조절주입 (TCI) 정맥마취제와근이완제는대부분다구획모형으로설명한다. 마취약제의이상적인용량요법은목표농도 C T 에빠르게도달하고그농도를유지하도록투여하는것이다. 목표농도조절주입은약물의투여속도를조절하여목표농도에접근한다. 정맥주입속도는초기에크고시간이지나면서점차감소하여일정한수준을유지한다. 정맥주입속도는시간에의존하며다음등식과같다 [16]. 등식 (28) 여기서 k 10 는소실속도상수, k 1j 와 k j1 는미세속도상수다. 주입기간증가하면정주속도는 C T V 1 k 10 를유지하며이것은약물의소실속도에해당한다. 예를들어, 환자 (40세, 70 kg/170 cm) 에게목표농도조절주입을사용하여 remifentanil의효과처농도가 3 ng/ml이되도록설정한다면 Fig. 6과같이초기의정주속도는 13 g/min 이지만점차감소하여 10분후에는약 7.3 g/min을유지한다. 효과처농도는약 5 분에 3 ng/ml 도달하고이후유지하는것을보여준다. 결 정맥마취제의약동학및약력학은약물을안전하게사용하고충분한효과를보증하는데도움이된다. 일반적으로부하용량, 유지용량및투여간격은약동학모수인분포용적, 청소율및반감기에기초하여결정한다. 환자에게약물의용량요법을결정할때환자의특성이고려되어야한다. TCI 는정맥마취제의특성과환자의특성을고려할수있는효과적인용량요법이다. 론 REFERENCES 1. Jang BW. Drug safety information. 45th ed. Seoul, KIDS. 2009, pp 63-5. 2. Jang BW. Drug safety information. 49th ed. Cheongwon, KIDS. 2011, pp 23-8. 3. Park JH, Kim HJ, Seo JS. Medicolegal review of deaths related to propofol administration: analysis of 36 autopsied cases. Korean J Leg Med 2012; 36: 56-62. 4. Avidan MS, Jacobsohn E, Glick D, Burnside BA, Zhang L, Villafranca A, et al. Prevention of intraoperative awareness in a high-risk surgical population. N Engl J Med 2011; 365: 591-600. 5.Leslie K, Chan MT, Myles PS, Forbes A, McCulloch TJ. Posttraumatic stress disorder in aware patients from the B-aware trial. Anesth Analg 2010; 110: 823-8. 6. Gillespie WR. Noncompartmental versus compartmental modelling in clinical pharmacokinetics. Clin Pharmacokinet 1991; 20: 253-62. 7. Jambhekar SS, Breen PJ. Basic pharmacokinetics. 2nd ed. London, Pharmaceutical Press. 2012, pp 13-5. 8. Mehvar R. The relationship among pharmacokinetic parameters: Effects of altered kinetics on the drug plasma concentration-time profiles. J Pharm Pharmaceut Sci 2004; 68: 1-9. 9. Jang GR, Harris RZ, Lau DT. Pharmacokinetics and its role in small molecule drug discovery research. Med Res Rev 2001; 21: 382-96. 10. Kinabo LD, McKellar QA. Current models in pharmacokinetics: applications in veterinary pharmacology. Vet Res Commun 1989; 13: 141-57. 11. Urso R, Blardi P, Giorgi G. A short introduction to pharmacokinetics. Eur Rev Med Pharmacol Sci 2002; 6: 33-44. 12. Jones HM, Parrott N, Jorga K, Lave T. A novel strategy for physiologically based predictions of human pharmacokinetics. Clin Pharmacokinet 2006; 45: 511-42. 13. Nestorov I. Whole body pharmacokinetic models. Clin Pharmacokinet 2003; 42: 883-908. 14. Hull CJ, Van Beem HB, McLeod K, Sibbald A, Watson MJ. A pharmacodynamic model for pancuronium. Br J Anaesth 1978; 50: 1113-23. 15. Toutain PL, Bousquet-Melou A. Volumes of distribution. J Vet Pharmacol Ther 2004; 27: 441-53. 16. Shafer SL, Varvel JR, Aziz N, Scott JC. Pharmacokinetics of fentanyl administered by computer-controlled infusion pump. Anesthesiology 1990; 73: 1091-102. 17. Scott JC, Ponganis KV, Stanski DR. EEG quantitation of narcotic effect: the comparative pharmacodynamics of fentanyl and alfentanil. Anesthesiology 1985; 62: 234-41. 18. Gepts E, Shafer SL, Camu F, Stanski DR, Woestenborghs R, Van Peer A, et al. Linearity of pharmacokinetics and model estimation of sufentanil. Anesthesiology 1995; 83: 1194-204. 19. Maitre PO, Vozeh S, Heykants J, Thomson DA, Stanski DR. Population pharmacokinetics of alfentanil: the average dose-plasma concentration relationship and interindividual variability in pati-
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