1、Chapter 1 Anesthetics,Anesthetic is a drug that causes reversible anesthesia and a loss of consciousness (including the feeling of pain). This allows patients to undergo surgery and other procedures without the distress and pain they would otherwise experience.,Local anesthetics General anesthetics,
2、Local anesthetic is used on specific nerve pathways , has effect of a loss of awareness of a part of the body. Whreas general anesthetic is used on central nervous system, has effect of a total unconsciousness.,1.1.1 Discovery and development of local anesthetics,Peruvian were known chewing coca lea
3、ves from South America for pain in 1532. An alkaloid was extracted from the leaves of coca and named Cocaine in 1860. Cocaine was used as a local anesthetic in clinic in 1884. Chemical structure was modified because of severe side-effect such as addiction, allergy, tissue irritating and unstable in
4、aqueous solution,1.1 Local anesthetics,Cocaine,Chemical modification of Cocaine,Studying results showed that benzoate fraction played the important role but methoxy carbonyl is not necessary for the activity of anesthesia. On the other hand, simplification of ecgonine led to the discovery of synthet
5、ic compounds -Eucaine and -Eucaine. This resulted that tropine was not necessary for the activity.,ecgonine,-Eucaine,-Eucaine,According to the obtained results, researchers begun to study the synthetic benzoic acid esters as the local anesthetics. First of all, Benzocaine was discovered in 1890. Sho
6、rtly after, Orthoform and Orthoform New were found with strong local anesthesia effect. At last,Procaine was discovered in 1904.,Benzocaine,Procaine,Orthoform,Orthoform New,Procaine hydrochloride,4-氨基苯甲酸-2-（二乙氨基）乙酯盐酸盐，又名盐酸奴佛卡因 4-Aminobenzoic acid 2-(diethylamino)ethyl ester monohydrochloride, or Nov
7、ocaine hydrochloride）,Physical properties: white crystal or crystalline powder, odorless, bitter taste and then a sense of paralysis. Mp.154 157 . Soluble in water (1:1), slightly soluble in ethanol (1:30) and chloroform, hardly soluble in ether.,Chemical properties: Hydrolysis: 酸、碱及体内酶均使其水解。pH3-3.5
8、最稳定，在碱性、中性及强酸性条件下易水解。 Oxidization：含芳伯氨基，易被氧化变色。,Activity and clinical application: Procaine 具有良好的局麻作用，毒性低，无成瘾性，是国内外临床广泛应用的局麻药之一，主要用于浸润麻醉，传导麻醉和封闭疗法。 With good local anesthesia, low toxicity and non-addiction Used for infiltration anesthesia, conduction anesthesia and closed treatment.,Synthesis of Pr
9、ocaine,Aromatic acid esters-Procaine and its derivatives,1.1.2 Classifications of local anesthetic,procaine,chloroprocaine,hydroxyprocaine,(1) Procaine的苯环上引入取代基，增加空间位阻使水解速率减慢，从而增加局麻作用。 Introduction of substituents on benzene ring of Procaine lead to increasing of the steric hindrance so slow down th
10、e hydrolysis to increase anesthesia.,parethoxycaine,tetracaine,(2) Procaine的苯环对位氨基被烷氨基或烷氧基取代，局麻作用增强，但毒性也增强。,(3) 侧链碳链改变可使稳定性增加，麻醉作用时间延长。,tutocaine,dimethocaine,thiocaine,(3) 羧酸酯中，以电子等排体S代替O，脂溶性增大，显效迅速。,1.1.2.2 Amides,lidocaine,prilocaine,trimecaine,盐酸利多卡因 Lidocaine Hydrochloride,N-（2，6-二甲苯基）-2-（二乙胺基）
11、乙酰胺盐酸盐一水合物 2-（Diethylamino）-N-(2,6-dimethylphenyl)acetamide hydrochloride monohydrate,Properties: white crystalline powder， odorless, bitter taste then a sense of numbness. Mp.75 79 , anhydrous complex mp.127 129 . soluble in water and ethanol, slightly soluable in chloroform (1:40), insoluble in et
12、her. pH of 0.5% aqueous solution is 4.0 to 5.5.,Lidocaine was firstly synthesized in 1943, used as a local anesthetic with anesthesia 2 9 times stronger than procaine and two times enduration time but also severe toxicity than procaine. Lidocaine also was found the effect of anti-arrhythmia.,Metabol
13、ism of Lidocaine,Synthesis of Lidocaine,1.1.2.3 Amino ketones,以电子等排体-CH2-代替酯基中的-O-，形成酮类化合物，不少氨基酮类化合物具有局麻作用。,Dyclonine,Falicaine,盐酸达克罗宁 Dyclonine hydrochloride,1-（4-丁氧苯基）-3-（1-哌啶基）-1-丙酮盐酸盐 1-（4-Butoxyphenyl）-3-(1-piperidinyl)-1-propanone hydrochloride,Dyclonine 具有强的麻醉作用和穿透力，作用快且持久，临床用作表面麻醉(surface anesthesia)。,Synthesis of Dyclonine,亲脂性部分以苯环的作用最强，其次为杂芳环，苯环上引入供电子基如氨基、烷基和烷氧基活性增强，引入吸电子基活性减弱.,亲水性部分大多为叔胺，也可为脂环胺，其中哌啶作用最强，氮原子上取代基碳原子总和3-5时作用最强.,中间连接部分，与麻醉作用时间与作用强度有关。当羰基部分为酮、酰胺、硫代酯或酯时，作用时间为：酮酰胺硫代酯酯。麻醉作用强度：硫代酯酯酮酰胺。,
