各三课件10神经系统药理

Autonomic

Pharmacology张纬萍浙江大学医学院药理2013.10.11第一次课的内容1、传出神经系统简介2、胆碱能神经系统胆碱受体激动药胆碱酯酶抑制药Nervous

System神经系统Nervous

SystemPeripheralNervousSystem

(PNS)CentralNervousSystem

(CNS)神经系统Nervous

SystemPeripheralNervousSystem

(PNS)CentralNervousSystem

(CNS)EfferentDivisionAfferentDivision神经系统Nervous

SystemPeripheralNervousSystem

(PNS)CentralNervousSystem

(CNS)EfferentDivisionAfferentDivisionSomatic

motorNervous

System神经系统Nervous

SystemPeripheralNervousSystem

(PNS)CentralNervousSystem

(CNS)EfferentDivisionAfferentDivisionAutonomic

nervousSystem

(ANS)Somatic

moNervous

Sytorstem神经系统Nervous

SystemPeripheralNervousSystem

(PNS)CentralNervousSystem

(CNS)EfferentDivisionAfferentDivisionParasympathetic副交感

Sympathetic

交感

Enteric

肠神经系统神经系统Autonomic

nervousSystem

(ANS)Somatic

motorNervous

System交感和副交感神经系统thoracolumbarcraniosacralThe

Enteric

Nervous

System肠神经系统(+SNS/PSNS)Absorptive

cell吸收细胞Enterochromaffin

cell肠噬铬细胞longitudinal

muscle

layer纵行肌Myenteric

plexus肌间神经丛Circular

muscle

layer环行肌Submucosal

plexus粘膜下神经丛Secretory

cell分泌细胞The

release

of

noradrenaline

has

the

following

effectsstimulates

heartbeatraises

blood

pressuredilates

the

pupilsdilates

the

trachea

and

bronchistimulates

the

conversion

of

liver

glycogen

intoglucoseshunts

blood

away

from

the

skin

and

viscera

to

theskeletal

muscles,

brain,

and

heartinhibits

peristalsis

in

the

gastrointestinal

(GI)

tractinhibits

contraction

of

the

bladder

and

rectumParasympathetic

stimulation

causesslowing

down

of

the

heartbeatlowering

of

blood

pressureconstriction

of

the

pupilsincreased

blood

flow

to

the

skin

and

visceraperistalsis

of

the

GI

tractNervous

SystemPeripheralNervousSystem

(PNS)CentralNervousSystem

(CNS)EfferentDivisionAfferentDivisionParasympatheticSympathetic(Enteric)神经系统Drugs

that

produce

their

primarytherapeutic

effect

by

mimicking

oraltering

the

functions

of

autonomicnervous

system

are

calledautonomic

drugs.Autonomic

nervousSystem

(ANS)Somatic

motorNervous

SystemNeurotransmittersdrugsReceptorsNeurotransmittersSynthesisStorageReleaseInactivationReceptorsActivationReceptorsdrugsDirect

actionsAgonists激动剂Antagonists拮抗剂NeurotransmittersSynthesisTransport

andstorageReleaseInactivationIndirect

actionsDirect-acting:

receptor

agonistsIndirect-acting:

increasingamounts

and/or

effects

oftransmittersDirect-acting:

receptor antagonistsIndirect-acting:

decreasingamounts

and/or

effects

oftransmittersMimeticsAntagonistsReceptorsdrugsDirect

actionsAgonists激动剂Antagonists拮抗剂NeurotransmittersSynthesisTransport

andstorageReleaseInactivationIndirect

actionsDirect-acting:

receptor

agonistsIndirect-acting:

increasingamounts

and/or

effects

oftransmittersDirect-acting:

receptor antagonistsIndirect-acting:

decreasingamounts

and/or

effects

oftransmittersMimeticsAntagonistsCholinergic

PharmacologyAdrenergic

PharmacologyCholine

UptakeACh

SynthesisCholine

acetyltransferase(ChAT)Choline

+

AcCoA

→

AChChATACh

StorageACh

ReleaseACh

EffectsPostsynapticPresynapticACh

MetabolismAcetylcholinesterase(AChE)ACh

→

Choline

+

AcetateAChECholinergic

TerminalRegulationby

auto-receptorsACh

acting

on

presynaptic

M2-cholinergic

receptorsby

hetero-receptorsNE

acting

on

presynaptic

a2-adrenergic

receptorsby

metabolism

(extra-neuronal)Acetylcholine

Releaseby

exocytosisCholinesterases胆碱酯酶Acetylcholinesterase

is

located

at

cholinergic

synapsesand

in

erythrocytes

(does

not

hydrolyze

succinylcholine)Pseudocholinesterase

(假性胆碱酯酶，synonyms:

plasmacholinesterase

or

butyrylcholinesterase丁酰胆碱酯酶)exists mainly

in

plasma,

liver

and

in

glia

(hydrolyzessuccinylcholine)Cholinergic

Receptors(cholinoceptors,

acetylcholine

receptors)Muscarinic

receptors

(M

receptors)M1,

3,

5

;

M2,

4G-protein

CoupledEnd

OrgansNicotinic

receptors

(N

receptors)NN

(N1)

receptors;

NM(N2

)

receptorsLigand-gated

Ion

ChannelsNMJ

&

GangliaM

receptors

:G-proteinCoupledMuscarinicReceptorSignalingPathwaysSmoothMusclecontractioncAMP↓(first,second,third

messenger)Heart

rate↓The

response

of

an

isolated

blood

vessel

to

ACh

dependson

whether

the

endothelium

is

intact

(unrubbed)

ormissingWhen

the

endothelium

is

present,

ACh

causes

smoothmuscle

relaxation

by

stimulating

the

production

of

nitric

oxide

(NO)

in

the

endotheliumIn

the

absence

of

the

endothelium,

a

small

amount

ofvasoconstriction

is

observed

——Fred

Murad,

1998M

receptors

:

end

organs

and

effect

of

activation血管平滑肌：收缩或舒张心脏：Depression

of

the

heart负性肌力：flNE释放负性频率：open

K+channel，›depolarization负性传导：AV

node

and

Purkinje

fibers缩短心房不应期：fl

AP

durationM

receptors

:

end

organs

and

effect

of

activationM

receptors

:

end

organs

and

effect

of

activation平滑肌：收缩(sensitive:

GI

tract,

bronchial,urinary

bladder;

insensitive:

uterine,

bloodvascular)

Mostly

smooth

muscle

contraction-

heart

being

the

main

exception外分泌腺：sensitive:

sweat,

tears,

salivary;insensitive:

GI

tract;Eye

(contraction

of

sphincter

muscle

of

iris:miosis缩瞳;contractionofciliarymuscle睫状肌收缩:contraction

for

near

vision)CNS:

activation，yet

ACh

can

hardly

pass

BBBNN

receptors（

N1

receptors

）Sympathetic

and

parasympathetic

gangliaAdrenal

medullaNM

receptors

（N2

receptors

） The

Neuromuscular

Junction

(NMJ) (Contraction

of

skeletal

muscles)N

receptors

:

subtypes

and

locationN

receptors

:Ligand-gated

Ion

ChannelsAt

theNMJ,

N

receptorsPentameric

with

fourtypes

of

subunits,

two

asubunits

bind

ACh

forligand

gatingAllothernAChRs,includingthoseat

theperipheralganglia,

have

2a’s

and

3b’sThe

NeuromuscularJunction

(NMJ)ABMyasthenia

Gravis重症肌无力This

means

“serious

disorder

the

NMJ”This

is

an

autoimmune

diseaseAntibodies

against

the

a

subunit

of

the

nAChRThe

ability

of

ACh

to

activate

the

nAChRs

isblocked

by

the

antibodiesAs

for

many

autoimmune

diseases,

stress

canmake

the

symptoms

worseTreatment

is

to

potentiate

cholinergic

signalingand

to

remove

the

antibodies

(blood

dialysis)M-

and

N-

ReceptorsdrugsDirect

actionsCholinoceptor

agonistsM,N

receptoragonists:acetylcholine，乙酰胆碱M

receptor

agonists:pilocarpine，匹鲁卡品N

receptor

agonists:nicotine，尼古丁AChCholinesterase

inhibitors(Anticholinesterases)Reversible:

neostigmine新斯的明Irreversible:organophosphatesIndirect

actionsCholinergic

antagonistsDrug

classificationCholinomimetics:Direct-acting

drugsAChEResistantAChDerivativesBondcleavedby

AChE乙酰胆碱乙酰甲胆碱卡巴胆碱氯贝胆碱Bethanechol

is

most

commonly

used,

particularly

post-operation

for

the

treatment

of

paralytic

ileus（麻痹性肠梗阻）

and

urinary

retention（尿储留）Cholinomimetics:Direct-acting

drugsNatural

Muscarinic

Agonists(Most

to

least

nicotinic)槟榔碱毒蕈碱amanita

muscaria(mushroom)匹鲁卡品毛果云香硷pilocarpus(S.

Amer.

shrub)areca

or

betal

nuts(India,E.

Indies)Amanita

muscaria

=>

muscarine“Food”

PoisoningAtropa

belladonna

=>

atropineDeadly

Nightshade,癫茄Pilocarpus=>PilocarpineAreca

nuts=>

ArecolinePoisoning

causes

muscarinic

overstimulationor

blocking

(for

belladonna

only)

salivation,

lacrimation(流泪),visualdisturbances;abdominal

colic

and

diarrheabronchospasm

and

bradycardiahypotension;

shockTreatment

is

with

atropine“Food”

PoisoningMuscarinic

Agonists:Parasympathetic

Effects

&

Therapeutic

UsesPilocarpine（1）EyesMiosis(缩瞳): contraction

of

sphincter

muscle

of

irisLowing

intraocular

pressure:

enlarging

angle

of

anterior

chamber,

increasing

drainage

of

aqueous

humorSpasm

of

modation(调节痉挛):contraction

of

ciliary

muscle,contraction

for

nearvisionlight睫状肌睫状体上皮细胞巩膜窦小梁网pilocarpinemiosismydriasisparalysis

ofmodationnear

sightspasm

ofmodationfar

sightatropineirisAnteriorchamberCiliary

muscle(contraction)zonuleCiliary

muscle(dilation)Canal

of

SchlemmzonuleposteriorchamberAnteriorchamberlens悬韧带aDisease

of

the

aging

eye

-increased

intraocular

pressure(IOP),

degeneration

of

theoptic

head,

and

restrictedvisual

field

typify

primaryopen-angle

aobstruction

of

the

aqueousdrainage

leads

to

elevated

IOP,and

may

result

in

atousdamage

to

the

optic

nerveMedical

Conditions

of

the

EyeCataracts

-

Clouding

of

thelensa

-

Loss

of

peripheral

or

“side”

visionMedical

Conditions

of

the

EyeMacular

Degeneration

-

Loss

of

central

or“straight

ahead”

visionDiabetic

Retinopathy

-

Blurring

of

centralvision

toblindnessaa

management

involves

lowering

IOP

by-

Decreasing

aqueous

production

by

the

ciliarybody-

Increasing

aqueous

outflow

through

thetrabecular

meshwork(小梁网)and

uveal

outflowpaths（房水排出通道）-

Neuroprotectionpilocarpine:

parasympathomimeticsincrease

aqueous

outflow

by

contraction

of

theciliary

muscle

to

increase

tone

and

alignment

ofthe

trabecular

networkPilocarpine

IncreaseAqueousHumor

OutflowMuscarinic

Agonists:Parasympathetic

Effects

&

Therapeutic

UsesPilocarpine（1）EyesMiosis(缩瞳): contraction

of

sphincter

muscle

of

irisLowing

intraocular

pressure:

enlarging

angle

of

anterior

chamber,

increasingdrainage

of

aqueous

humorPilocarpinePromoting

secretion

of

exocrine

glands,especially

in

sweat,

salivary

and

tear

glandsGastrointestinal

tract:

increasing

tone

and

motilityUrinary

tract:

contraction

of

bladder

and

relax

for external

sphincter

musclesRespiratory

system:

bronchoconstriction

andsecretion(5)

CNS:

cortical

arousal

or

activationMuscarinic

Agents:Parasympathetic

Effects

&

Therapeutic

UsesOphthalmological

usesa(青光眼):

(concentration

≤

2%)narrow

(closed)-

or

wide

(open)-anglesit

is

the

drug

of

choice

in

the

emergency

lowering

ofintraocular

pressureIritis

(虹膜炎):

miotics（缩瞳）/mydriatics（扩瞳）Other

useGastrointestinal

disorders,

like

gastroparesisUrinary

bladder

disorders,

urinary

retentionXerostomia（口腔干燥）,Antidote for

atropine

poisoningMuscarinic

Agents:Parasympathetic

Effects

&

Therapeutic

Uses-

actions

at

ganglia,

NMJ,

brainActions

are

complex

and

frequentlyunpredictable,

because

of

the

varietyof

neuro-effector

sites

and

becausenicotine

both

stimulates

and

desensitizes

effectors.

Nicotinetypically

will

affect

the：Periphery:

›HR,

›BP,

›

GI

tone

&

motilityand

alsoCNS:

stimulation,

tremors,›

respiration,

emetic

effectsThe

addictive

power

of

cigarettes

is

directly

related

to

theirnicotine

content.N

receptor

agonists:Nicotine1

Cholinomimetics(Parasympathomimetics)(1)

Direct-acting

drugs:

Cholinoceptor

agonistsM,

N

receptor

agonists:

acetylcholineM

receptor

agonists:

pilocarpineN

receptor

agonists:

nicotineIndirect-acting

drugs:

Cholinesterase

inhibitors(Anticholinesterases)Reversible:

neostigmineIrreversible:

organophosphatesDrug

classificationDrug

classification1

CholinomimeticsDirect-acting

drugs:

Cholinoceptor

agonistsM,

N

receptor

agonists:

acetylcholineM

receptor

agonists:

pilocarpineN

receptor

agonists:

nicotineIndirect-acting

drugs:

Cholinesterase

inhibitors(Anticholinesterases)Reversible:

neostigmineIrreversible:

organophosphatesCholinergicantagonists：

Cholinesterasereactivatorspralidoxime

iodideCholinomimetics-Indirect

Agents:AChE

InhibitorsAcetylcholinesterase

(AChE)

Activity酯解部位 阴离子部位乙酰化AChE胆碱水解Edrophonium依酚氯铵(reversible,competitive)Carbamates

氨甲酰类(slowly

reversible)Organophosphates

有机磷类(irreversible)Cholinomimetics-

Indirect

Agents:AChE

Inhibitorsneostigmine新斯的明异氟磷

These

agents

areirreversibleandare

usedaspesticides

or

fora毒扁豆碱依酚氯铵These

agents

arereversible

and

areused

medically

(

a

orMG)氨甲酰酚羟基Acetylcholinesterase

Inhibitors:ReversibleEdrophonium

依酚氯铵Rapidly

absorbed;A

short

duration

of

action

(5-15min);Competitive

(reversible)Used

in

diagnosis

of

myasthenia

gravis.Excess

drug

may

provoke

a

cholinergiccrisis,

Atropine

is

the

antidote.Inhibitory

Effects

are

slowlyreversibleRepresentative

Drugsneostigmine

新斯的明

(quaternary

amine)physiostigmine

毒扁豆碱

(tertiary

amine)pyridostigmine吡斯的明

(quaternary

amine)quaternary

amines

effective

in

periphery

onlytertiary

amines

effective

in

periphery

and

CNS（fat-soluble）二甲氨基甲酰化AChEAcetylcholinesterase

Inhibitors:

Carbamates氨甲酰类Acetylcholinesterase

Inhibitors:

Carbamatesneostigmine

(quaternary

amine)–

Pharmacological

effectsAChE(-), ACh

↑, directly

stimulating

NMRstronger

effect

on

skeletal

muscleseffective

on

GI

tract

and

urinary

bladdermore

polar

and

can

not

enter

CNSrelatively

ineffective

on

CVS,

glands,

eyeAcetylcholinesterase

Inhibitors:

Carbamatesneostigmine

(quaternary

amine)–

Clinical

usesMyasthenia

gravis:

symptomatic

treatment,overdose:cholinergic

crisisParalytic

ileus

and

bladder:post

operative

abdominaldistension

and

urinary

retentionParoxysmalsuperventricular

tachycardia（阵发性室上速）Antidote

for

tubocurarine

（筒箭毒碱）

and

related

drugpoisoningneostigmine

(quaternary

amine)–

Adverse

effectsCholinergic

effects:

muscarinic

and

nicotinic

effects,treated

with

atropine

(muscarinic)Contraindications： mechanical

ileus

机械性肠梗阻

urinary

obstruction

泌尿道梗阻

bronchial

asthma

支气管哮喘poisoning

of

depolarizing

skeletal

muscle

relaxants(e.g.succinylcholine琥珀胆碱)Acetylcholinesterase

Inhibitors:

CarbamatesOther

reversible

AChE

inhibitorsPyridostigmine吡斯的明Similar

as

neostigmine,

slow

but

longer

durationPhysostigmine毒扁豆碱Stronger

than

neostigmineNo

direct

action

on

M

and

N

receptorCan

enter

CNS,先兴奋后抑制Stimulate

N

receptor

of

sympathetic

nervous

node

ficomplex

effects

on

cardiovascular

systemStimulate

N

receptor

of

skeletal

muscle

fi

肌束震颤主要用于急性青光眼，抗胆碱药中毒，但其本身的毒性较大。Other

reversible

AChE

inhibitorsGalanthamine加兰他敏Similar

as

neostigmine,

can

enter

CNS

and

treat

forADDihydrogalanthamine二氢加兰他敏

Ambenonium

chloride安贝氯胺Demecarium

bromide地美溴铵

Distigminebomide溴地斯的明Eseridine依舍立定Eptastigmine依斯的明对硫磷马拉硫磷梭曼These

agents

areused

aspesticides

or

fora

or

for

biothreatAcetylcholinesterase

Inhibitors:IrreversibleBond

is

hydrolyzedin

binding

totheenzyme乙膦硫胆碱For

ophthalmic

useAcetylcholinesterase

Inhibitors:OrganophosphatesEffects

ofOrganophosphates

areirreversible

(covalentbond

formation)Pralidoxime(碘解磷定)canrestore

AChE

activity

ifadministered

soon

after

toxin

exposure.Conjugating

withorganophosphate

by

oximegroup;Conjugating

with

freeorganophasphates异氟磷解磷定单烷氧基磷酰化AChE老化(1)

Toxic

symptoms–

Acute

intoxicationMuscarinic

symptoms

eye,

exocrine

gland