Chapter 7 Analgesics and Anesthetics(2)

Chapter 7 Chapter 7 Analgesics and Anesthetics(2)Analgesics and Anesthetics(2)

Shanghai Jiao Tong University

7.2.1 Introduction

Part 2 AnestheticsPart 2 Anesthetics

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


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


Discovery of anesthetic agents in middle of 19th century

Chemicla ( ether 、 chloroform 、 nitrous oxide)—recreation


First time surgical operation under the condition of anesthesia

1946-10-16

W. T. G.Morton

C. T. Jackson


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


7.2.2 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.

Stage 1: AnalgesiaAnalgesia (depends on drug)AmnesiaEuphoria

Stage 2: Delirium ExcitementDeliriumCombative behavior

Stage 3: Surgical AneshesiaUnconsicousnessRegular respirationDecreasing eye movement

Stage 4: Respiratory Paralysis Medullary depression Respiratory arrest Cardiac depression and arrest No eye movement

Awake

CommenceSurgery

SurgeryComplete

Awake

Dee

peni

ng a

nest

hesi

a

Rec

ove r

yt f r

om a

n est

hesi

a


Gases 1-1 Xe Xenon

1-2 N2O Nitrous oxide

1-3 Cyclopropane

Volatile

1-4 ( C2H5)2O Diethyl ether

1-5 CHCl3 Chloroform

Gases and volatile

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.

1) Inhalation Anesthetics


Halogenated hydrocarbons or ethersHalothane 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.

Generic Name Structure Boiling Point ( )℃

Chemically Stablea

Desflurane (Suprane)( 地氟烷） F2HC–O–CHF–CF3 23.5 Yes

Enflurane (Ethrane) （恩氟烷） F2HC–O–CF2–CHFCl 56.5 Yes

Halothane(Fluothane) （氟烷） F3C–CHBrCl 50.2 No

Isoflurane (Forane) （异氟烷） F2HC–O–CHCl-CF3 48.5 Yes

Methoxyflurane （甲氧氟烷） H3C–O–CF2–CHCl2 104.7 No

Sevoflurane (Ultane) （七氟烷） (CF3)2CH–O–CH2F 58.5 No

a Indicates stability to soda lime, ultraviolet light, and common metals.


2 ） parenteral Anesthetics

O

NH

Cl

CH3

NH

N

O

O

SNa

H3C

H3C

H3CH3C O

O

N

N

H3COH CH3

CH3H3C

H3C

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


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 )”.

Cl

NHCH3O.HCl

1

2

3

45

6

【 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


Synthetic route

NCl

HO

HCH3

O Cl O Cl

Br

NH2CH3

NCH3Cl

OHDecahydronaphthalene

Br2

HCl

ONHCH3

Cl. HCl

CNCl

MgBr

+


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）


古柯

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

1) The Discovery of Local Anesthetics

ON

CH3 COOCH3

H

¿É¿¨ ÒòCocaine

ÍÐßß¿¨ ÒòTropacocaine

o

ON

CH3

H o


2) Structure modification of Cocaine

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.

COO

N CH3

COOCH3

OHN CH3

COOH

CO

OHN

H3C

H3CH3C

CO

OHN

H3C

H3C

H3C H3C

COO

N CH3

COOCH3

H2O +

COOH

(-)-Egonine

Eucaine Eucaine

H2N COOC2H5H2N COOCH2CH2NC2H5

C2H5

Procaine Hydrochloride Benzocaine

.HCl

优卡因

爱康宁


1. Aromatic acid esters (Procaine) 2. Amides （ lidocaine ）3. Amino Ketones （ Dyclonine ）4. Amino Ethers (Pramocaine)

3) Structure type of synthetic Local Anesthetics

H2N COOCH2CH2NC2H5

C2H5

Procaine( 普鲁卡因）

NHCOCH2NC2H5

C2H5

CH3

CH3

Lidocaine （利多卡因）C4H9O

N

O

Dyclonine （达可罗宁）

C4H9O

O NO

pramoxine （普莫卡因）


4 ） Structure-activity relationship （ SAR ）

H2N

CH3

CH3

procaine

lidocaine

cocaine

N

COOCH3lipophilic portion intermediate

chain

hydrophilic portion

O

ON

CH3

HN

ON

O

O


Lipophilic portion

R1

YZ N

R3

R2

n

亲脂部分

NH S O

> > >

When para or ortho posi ti on have el etron donati ng gruop, acti vi ty i ncreased

The lipophilic center is usually either a carbocyclic or heterocyclic ring system


Hydrophilic portion

R1

YZ N

R3

R2

n

亲水部分

hydrophilic center is normally a secondary or tertiary amine, which may or may not be cyclic. Tertiary amines are more useful since they are less irritating to tissue.


Intermediate chain

R1

YZ N

R2

n

中间部分

Stabi l i ty:C OO

CO

S CO

HN C

O H2C

C OO

CO

S CO

HNC

O H2C

< < <

>> >Activity:

2-3 carbon atoms short hydrocarbon chain,


External membrane

B H BH

B H BH

b TTX.STX binging site

local anesthetics receptor

selective site

B

a

a

b'

Internal membrane

5) Model of a sodium channel, as suggested by Hille, depicting a hydrophilic pathway and a hydrophobic pathway

C

O

OH2C

H2C N

H+

CH3

CH3_

Van der Waal,forces

Permanent dipole-dipole attraction

Van der Waal,forces

Van der Waal,forces

Electrostatic attraction

R

Voltagegated sodium chennels

（电压门控钠离子通道）


【 Procaine Hydrochloride 盐酸普鲁卡因】

H2N

O

ON

CH3

CH3

HCl

Chemical name ：4-Aminobenzoic acid 2-(diethylamino)ethyl ester hydrochloride4- 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） .


Retrosynthetic Analysis

O2N COOH

H2N C OO

CH2CH2 NC2H5

C2H5

HO CH2CH2 NC2H5

C2H5+

O2N CH3 HNC2H5

C2H5

O +

H2N C OO

CH2CH2 X HNC2H5

C2H5

+

O2N COOH

O2N CH3

+ HO CH2CH2 X


HNC2H5

C2H5

O +C2H5OH

NC2H5

C2H5

HOH2CH2C

Synthetic route

CH3

NO2

Na2Cr2O7, H2SO4

COOH

NO2

HOCH2CH2N(C2H5)2

xylene

HCl

O2N

O

ON

CH3

CH3

H2N

O

ON

CH3

CH3

1) Fe/HCl

H2N

O

ON

CH3

CH3

HCl2) NaOH


CH3 HN

CH3O

N CH3

CH3

.HCl. H2O

【 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 eutectic mixture （共融混合物） that is very popular with pediatric patients.


CH3 HN

CH3O

N CH3

CH3

H3CNH2

CH3ClCH2COCl

H3CNHCOCH2Cl

CH3NH(CH2CH3)2

HCl

CH3 HN

CH3O

N CH3

CH3

HCl

HN

ON

Synthetic route


metabolism

OH

CH3

CH3

NH

O

N

CH3

CH3

OH

CH3

CH3

NH

OHN CH3

CH3

CH3

NH

O

N

CH3

CH3CH3

CH3

NH

OHN CH3

Conjugates Conjugates

3-Hydoxymomnoethyllidocaine3-Hydoxylidocaine

CYP1A2CYP1A2

LidocaineCNS toxicities

N-dealkylation

CNS toxicities

CH3

O

H

CYP1A2monoethylglycinexylidide

CH3

O

H

CH3

CH3

NH

O

NH2

NH2

CH3

CH3

NH2

CH3

CH3

HO

NH2

CH3

COOHConjugates

glycinexylidide

(No CNS toxicity)


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 )

O

H3CO

HO

alphaxalone

NH

HNCH3Br

H3COO

2-bromomelatonin


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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Chapter 7 Analgesics and Anesthetics(2)