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系統識別號 U0026-3107201916202500
論文名稱(中文) 麻醉藥物之藥代動力學及藥效動力學研究
論文名稱(英文) Pharmacokinetic and Pharmacodynamic Studies in Anesthetics
校院名稱 成功大學
系所名稱(中) 臨床藥學與藥物科技研究所
系所名稱(英) Institute of Clinical Pharmacy and Pharmaceutical sciences
學年度 107
學期 2
出版年 108
研究生(中文) 周文英
研究生(英文) Wen-Ying Chou
學號 TB8971010
學位類別 博士
語文別 英文
論文頁數 101頁
口試委員 指導教授-周辰熹
共同指導教授-曾稼志
口試委員-陳貞吟
口試委員-吳之芾
口試委員-王祈斐
中文關鍵字 麻醉藥物  藥物代謝動力學  藥物效應動力學 
英文關鍵字 Anesthetic  Pharmacokinetic  Pharmacodynamic 
學科別分類
中文摘要 目的:
藥物代謝動力學被描述為 "身體對藥物的影響" (藥物濃度) 和藥物效應動力學被描述為 "藥物對身體的作用" (反應)。對於麻醉藥物, 可能用到麻醉前給藥、圍手術期抗生素、用於誘導或維持的靜脈注射劑、吸入麻醉劑、阿片類藥物、肌肉鬆弛劑、神經肌肉傳導逆轉和術後鎮痛藥, 很多種類的藥物給予。由於麻醉劑的濃度影響麻醉的深度, 麻醉醫師應需相當瞭解這些藥物的機制和相互作用, 以達到所需的濃度及避免不良副作用, 作為麻醉學的安全實踐。
方法:
研究的患者年齡在 25-65 歲, 從高雄長庚紀念醫院或國立成功大學醫院招募。
在第一部分, 藥物代謝動力學, 我們在手術中為不同體重指數 (BMI) 的患者測量吸入麻醉氣體 (七氟醚) 的吸氣和呼氣 (潮氣末端) 濃度; 並調查性別和mu-1 阿片類受體A118G多樣性之間的可能的關聯。在第二部分, 藥物效應動力學: 觀察反應,我們測量接受麻醉藥物後的患者在術後第一個晚上匹茲堡睡眠品質指數(PSQI)的評分,記錄7組分數的變化;還研究了患者控制鎮痛器 (PCA) 的最佳劑量, 以達到嗎啡的不良反應和鎮痛效果的最佳平衡。
結果:
第一部分,藥物代謝動力學,不同的體重指數 (BMI) 可能會影響七氟醚用於短期手術的沖入和洗出曲線,但可能不是與恢復清醒相關的主要因素。與 AA 和 AG 基因型患者相比, OPRM1 G118G 基因型的女性患者在全膝關節置換術後需要更多的嗎啡進行術後疼痛控制, 但男性患者的這三種基因型在嗎啡消耗量方面沒有明顯差異。在第二部分, 藥物效應動力學, 對於異丙酚麻醉後接受小型婦科手術的女性門診患者, 他們術後 PSQI 評分得到改善, 七組中有五組分數(睡眠時間、睡眠障礙、睡眠潛伏期、睡眠品質和使用睡眠藥物)變得更好, 但另外兩組分數沒有(效率和白天功能障礙)。對於術後睡眠障礙, 與七氟醚組相比, 丙泊酚和七氟醚對這些 ASAI-II 女性患者術後 PSQI 評分有不同的影響。
結論:
對於麻醉醫師來說, 瞭解任何麻醉劑的藥物代謝動力學和藥物效應動力學的變化是基於為了避免麻醉藥物的治療濃度無意間給得太過或不足,因此,確保患者免於受到傷害,需要在藥物代謝動力學和藥物效應動力學方面進行戰略應用,以達到麻醉及止痛藥物的最佳深度及最少副作用。
英文摘要 Objective:
Pharmacokinetics is described as “what the body does to the drug” (drug concentration) and pharmacodynamics is described as “what the drug does to the body” (response). For anesthetics, taking into account premedication, perioperative antibiotics, intravenous agents used for induction or maintenance, inhalational anesthetics, opioids, muscle relaxants, reverse for neuromuscular transmission and postoperative analgesics, so many kinds of drugs are given. Because the concentration of anesthetics would indicate the depth of anesthesia, anesthesiologists should deliberately understand the mechanisms and avoid the adverse effects and interactions of these drugs to achieve the desired concentration for a safe practice of anesthesiology.

Methods:
All of the patients of the study, aged 25-65, were recruited from the Chang Gung Memorial hospital, Kaohsiung branch or the National Cheng Kung University Hospital. In the first part, pharmacokinetic, we measured the inspiratory and expiratory (end-tidal) concentration of inhaled anesthetic (sevoflurane) for patients with different body mass index (BMI) during surgery and investigated the possible associations between the genders and the mu-1 opioid receptor polymorphism A118G. In the secondary part, pharmacodynamics, to observe the response, we measured the changes of the 7-componets in Pittsburgh Sleep Quality Index scores for the first postoperative night after anesthesia; we also investigated the optimal dose of patient controlled analgesia (PCA) to get a balance between the adverse effects and analgesia from morphine.
Results:
In the first part, the different BMIs could affect the wash-in and wash-out curves of sevoflurane for a short term surgery but might not a major factor associated with the recovery profiles. Female patients of homozygous G118G of OPRMI required more morphine from PCA device for post-operative pain control after total knee replacements in comparison with patients of AA and AG genotypes but no significant difference in morphine consumption among these genotypes for male patients.
In the secondary part, for female outpatients undergoing minor gynecologic surgery after propofol anesthesia, their postoperative PSQI scores improved, five components (sleep duration, sleep disturbance, sleep latency, sleep quality, and use of sleep medications) became better but not another two components (efficiency and daytime dysfunction). For postoperative sleep disorder, compared with the sevoflurane group, our findings indicated that propofol and sevoflurane have different impacts on postoperative PSQI scores for these ASA I-II female patients undergoing minor gynecologic surgery in the first night. For female receiving PCA with intravenous opioid following gynecological surgery, beyond 30 mg morphine in the postoperative 24 hours, we could replace opioid with non-opioid analgesic to help reducing morphine consumption and get a balance between analgesia and adverse effects.
Conclusion:
For an anesthesiologist, it is a responsibility to understand the basis for alteration in the pharmacokinetics and pharmacodynamics of any anesthetic used to avoid unintentional supra-therapeutic or sub-therapeutic concentration for anesthesia, the strategically employment in pharmacokinetics and pharmacodynamics to achieve the optimal depth of anesthesia is needed to secure the patient against the harm and to lessen the adverse effects from anesthetics and analgesics.
論文目次 Abstract.................................................................................................................................................I
中文 摘 要…..........................................................................................................................................III
誌 謝….....................................................................................................................................................V
Table of Contents..................................................................................................................................VIII
Figure of Contents.……………..................................................................................................................IX
Abbreviation.……………............................................................................................................X

1. Preface……………….….....................................................................................................................1

2. PART I............................................................................................................................................3
I-(1) Wash-in and wash-out for sevoflurane in Patients with different body
mass indexes…………………………………………………………………………………………………3

I-(1) .1 Abstract .....................................................................................................................4
I-(1) .2 Introduction ..............................................................................................................6
I-(1) .3 Methods.............................................................................................................7
I-(1) .4 Results..............................................................................................................9
I-(1) .5 Discussion...................................................................................................................11

I-(2) A118G Polymorphism of OPRM1 Gene Caused Different Morphine Consumption
for Post-operative Pain Control in Female Patients after Total Knee Replacement…………………24
I-(2) .1 Abstract ........................................................................................................................................25
I-(2) .2 Introduction .................................................................................................................................27
I-(2) .3 Materials and Methods.................................................................................................................28
I-(2) .4 Results..........................................................................................................................................31
I-(2) .5 Discussion.....................................................................................................................................33

3. PART Ⅱ...............................................................................................................................................42
II-(1) What changes in Pittsburgh Sleep Quality Index scores on first postoperative night for outpatients after minor gynecologic surgery under propofol anesthesia?....42

II-(1) .1 Abstract .......................................................................................................................................43
II-(1) .2 Introduction ................................................................................................................................44
II-(1) .3 Materials and Methods...............................................................................................................45
II-(1) .4 Results.........................................................................................................................................47
II-(1) .5 Discussion....................................................................................................................................49

II-(2) Comparing the different impacts of propofol and sevoflurane anesthesia on sleep
quality in the first postoperative night following minor gynecologic surgery……..…55

II-(2) .1 Summery.............................................................................................................................56
II-(2) .2 Introduction ......................................................................................................................57
II-(2) .3 Methods..........................................................................................................................59
II-(2) .4 Results.................................................................................................................................61
II-(2) .5 Discussion........................................................................................................................63

II-(3) A Balance between Analgesia and Side Effects caused by Intravenous Morphine
from Patient-controlled Analgesia for Elective Gynecologic Surgery …........................71

II-(3).1 Abstract ...........................................................................................................................72
II-(3).2 Introduction ...................................................................................................................74
II-(3).3 Methods.............,...........................................................................................................75
II-(3).4 Results...........................................................................................................................77
II-(3).5 Discussion......................................................................................................................78

4. Perspectives of personalized medicine for anesthesia…….....................................................83
5. REFERENCES ...........................................................................................................................................84
Pittsburgh Sleep Quality Index scores…………………………………………............95 BIBLIOGRAPHY...............................................................................................................................................98

Table of Contents

Table I-(1).1 Demographic data for patients with different BMI…………………………………………………15
Table I-(1).2 The relationships between the parameters and the awaken effects ……………………...16
Table I-(1).3 Time needed to recovery for groups with different BMIs ……………………………….………17

Table I-(2).1 Demographic data of the female / male patients for different genotypes of OPRM1 gene…39
Table I-(2).2 Consumed morphine dose (mg), dosage (mg/kg) and Demands for the female/male patients
who received patient-controlled analgesia............…….…..…………………….…………..….40
Table I-(2).3 Side effects for the female/male patients who received patient-controlled analgesia……..41

Table II-(1).1 The demographic characteristics of 81 enrolled patients......................................................51
Table II-(1).2 Wilcoxon signed-rank test to compare PSQI scores and subscales for individual components of PSQI between preoperative and postoperative data……………………………………………………52
Table II-(1).3 Comparison for sleep latency, sleep duration and go-to-bed time between preoperative data
and postoperative data with Paired Samples Test………………………………………..……………..53
Table II-(1).4 Multivariate regression analysis for the predictors of postoperative Pittsburgh Sleep
Quality Index (PSQI) scores after propofol anesthesia………….………………………………………..54

Table II-(2).1 Mean and range of demographic characteristics of the propofol and the sevoflurane anesthesia groups. The demographic characteristics of 81 enrolled patients.....................66
Table II-(2).2 Wilcoxon Signed Ranks Test for scores between independent groups and related samples……………………67
Table II-(2).3 Compared the sleep latency before and after propofol anesthesia with paired t test…68
Table II-(2).4 Compared the sleep latency and daytime dysfunction before and after sevoflurane
anesthesia with paired t test and Wilcoxon Signed Ranks Test………………………..69

Table II-(3).1 The demographic data, and dose of morphine and side effects........................................81





Figure of Contents

Figure I-(1) .1 The inspiratory concentration of sevoflurane measured for three groups during the first half an hour of the wash-in period………………………………...18
Figure I-(1).2 The expiratory concentration(FA) for sevoflurane during the first half an hour of the wash-in period…..19
Figure I-(1).3 The difference (FI-FA) between the inspiratory concentration and the expiratory concentration for sevoflurane during the first half an hour of the wash-in period…………………………20
Figure I-(1).4 The wash-in curve of sevoflurane during administration in 25 minutes……………………..21
Figure I-(1).5 The wash-out curve of sevoflurane during elimination in 5 minutes……………22
Figure I-(1).6 The wash-out curve of sevoflurane during elimination in 5 minutes on logarithmic scale..........23

Figure I-(2).1 Pain assessment by female patients………….......……37
Figure I-(2).2 Pain assessment by male patients…………….......………38

Figure II-(2) .1 The distribution of PSQI change among patients receiving propofol and sevoflurane anesthesia………..70

Figure II-(3) .1 The distribution of total morphine dose of 24 hours in different severity group of pruritus……………82
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PART II-(2) Reference
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4. Tung A, Bergmann BM, Herrera S, Cao D, Mendelson WB. Recovery from sleep deprivation occurs during propofol anesthesia. Anesthesiology 2004;100:1419-1426.
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