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Chapter 7 Analgesics and Anesthetics(2)

Chapter 7 Analgesics and Anesthetics(2). Part 2 Anesthetics. 7.2.1 Introduction. Anesthetics are used to depress the peripheral and central nervous systems (CNS) by blocking nerve conduction in order to facilitate surgical and other noxious procedures. Classification:.

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Chapter 7 Analgesics and Anesthetics(2)

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  1. Chapter 7 Analgesics and Anesthetics(2)

  2. Part 2 Anesthetics 7.2.1 Introduction Anesthetics are used to depress the peripheral and central nervous systems (CNS) by blocking nerve conduction in order to facilitate surgical and other noxious procedures. Classification: general Anesthetics (inhalation and intravenous) : Inducing a loss of waking consciousness in humans similar in many respects to sleep. Local Anesthetics: block local nerve conduction with waking consciousness

  3. Surgical operation before the use of Anesthetics（in 18th century）

  4. Discovery of anesthetic agentsin middle of 19th century Chemicla ( ether、chloroform、nitrous oxide)—recreation

  5. First time surgical operation under the condition of anesthesia 1946-10-16 W. T. G.Morton C. T. Jackson

  6. Morton 在他之前 手术始终是死亡的痛苦， 在他之时 痛苦得到了防止和避免， 在他之后 科学制服了疼痛。 Henry Jacob Bigelow

  7. 7.2.2 General Anesthetics General anesthetics depress the central nervous system to a sufficient degree to permit the performance of surgery and other noxious or unpleasant procedures. Not surprisingly, general anesthetics have low therapeutic index and thus require great care in administration. Anesthesiologists also employ sedatives, neuromuscular blocking agents, and local anesthetics as the situation requires.

  8. 1)Inhalation Anesthetics Diethyl ether one of the first agents to be introduced as an anesthetic(1842), has high potency with significant analgesic and neuromuscular relaxing effects. But this agent is flammable, and when mixed with air, oxygen, or nitrous oxide, it is explosive. Induction is very slow; Irritation of the respiratory tract may lead to excessive bronchial secretions complicating . recovery is similarly prolonged. Gases and volatile

  9. Halogenated hydrocarbons or ethers Halothane was introduced into medical practice in the United States in 1956 as a nonflammable, nonexplosive, halogenated volatile anesthetic that usually is mixed with air or oxygen. Several non nonflammability halogenated hydrocarbons volatile anesthetics were developed in last century.

  10. 2） parenteral Anesthetics The parenteral general anesthetics, administered by the intravenous route. Nonflammable, nonexplosive, chemical stable,no Irritation of the respiratory tract. But anesthetic depth is not controled easily Propofol 异丙酚 ketamine氯胺酮 etomidate 依托咪酯 Thiopental 硫喷妥

  11. 【Ketamine Hydrochloride 盐酸氯胺酮】 Chemical name: 2-(2-Chlorophenyl)-2-(methylamino) cyclohexanone hydrochloride 2-(2-氯苯基)-2-(甲氨基)-环己酮 Action: Ketamine hydrochloride is an injectable, very potent, rapidly acting anesthetic agent. It does not relax skeletal muscles and, therefore, can only be used alone in procedures of short duration that do not require muscle relaxation. Recovery from anesthesia may be accompanied by “emergence delirium(自发性神经错乱)”.

  12. Synthetic route

  13. 7.2.3 Local Anesthetics A local anesthetic agent is a drug that, when given either topically or parenterally to a localized area, produces a state of local anesthesia by reversibly blocking the nerve conductances that transmit the feeling of pain from this locus to the brain with waking consciousness. Surface anesthesia (表面麻醉) Infiltration anesthesia (侵润麻醉 ) Conduction block anesthesia (传导阻滞麻醉）

  14. 1) The Discovery of Local Anesthetics As early as 1532, the anesthetic properties of coca leaves (Erythroxylon coca Lam) became known to Europeans from the natives of Peru, who chewed the leaves for a general feeling of well-being and to prevent hunger. Saliva from chewing the leaves often was used by the natives to relieve painful wounds. The active principle of the coca leaf, however, was not discovered until 1860 by Niemann, who obtained a crystalline alkaloid from the leaves, to which he gave the name cocaine 古柯

  15. 2) Structure modification of Cocaine 优卡因 爱康宁 Benzoyl esters of amino alcohols exhibited strong local anesthetic properties without any addicting liability.for example α-eucaine and β-eucaine. Removal of the 2-carbomethoxy group of cocaine such as tropacocaine also maintained activity but abolished the addicting liability.

  16. 3) Structure type of synthetic Local Anesthetics 1. Aromatic acid esters (Procaine) 2. Amides （ lidocaine ） 3. Amino Ketones （Dyclonine） 4. Amino Ethers (Pramocaine) Procaine(普鲁卡因） Lidocaine（利多卡因） Dyclonine（达可罗宁） pramoxine（普莫卡因）

  17. 4）Structure-activity relationship（SAR）

  18. Lipophilic portion

  19. Hydrophilic portion

  20. Intermediate chain

  21. 5) Model of a sodium channel, as suggested by Hille, depicting a hydrophilic pathway and a hydrophobic pathway Voltagegated sodium chennels （电压门控钠离子通道）

  22. 【Procaine Hydrochloride 盐酸普鲁卡因】 Chemical name： 4-Aminobenzoic acid 2-(diethylamino)ethyl ester hydrochloride 4-氨基苯甲酸-2-（二乙氨基）乙酯盐酸盐 Clinical use ： Procaine is the first synthetic local anesthetic and was introduced into use in 1905. It has been replaced by newer generations of local anesthetics, its use being reserved for infiltration anesthesia(侵润麻醉） and diagnostic nerve blocks（诊断性神经节阻断）.

  23. Retrosynthetic Analysis

  24. Synthetic route

  25. 【Lidocaine Hydrochloride 盐酸利多卡因】 Chemical name： 2-(diethylamino)-N-(2,6-dimethylphenyl) acetamide hydrochloride monohydrate N-（2，6-二甲基苯基）-2-（二乙氨基）乙酰胺盐酸盐一水合物 Action： Lidocaine is the most commonly used amino amide-type local anesthetic. It is very lipid soluble and, thus, has a more rapid onset and a longer duration of action than most amino ester-type local anesthetics, It can be administered parenterally or topically either by itself or in combination with prilocaine(丙胺卡因） or etidocaine（依替卡因） as a eutecticmixture（共融混合物） that is very popular with pediatric patients.

  26. Synthetic route

  27. metabolism

  28. 7.2.4 Unmet Medical Needs Local Anesthetic Side Effects （less cardiotoxic） Rapid-Offset Intravenous Anesthetics Long-Lasting Side Effects of Inhaled Anesthetics（decrements in mental performance智力功能减退） 7.2.5 New Research Areas Anesthetic-Specific Benzodiazepines (BZs) alphaxalone (阿法沙龙, α-羟孕双酮 ) Melatonin analogs 2-bromomelatonin (2-溴褪黑素) alphaxalone 2-bromomelatonin

  29. 本节重点内容 1、麻醉药的定义和分类 2、卤代烷类吸入麻醉药的特点和常用的吸入麻醉药 3、静脉全身麻醉药的特点和常用药物 4、局麻药的发展，可卡因的结构改造和普鲁卡因的发现 5、局麻药的构效关系 6、代表性药物（盐酸氯胺酮、盐酸普鲁卡因、盐酸利多卡因）的结构、化学名、合成、代谢、用途。

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