pharmacology General introduction Drugs acting on efferent nervous system Drugs acting on central nervous system Drugs acting on cardiovascular system Drugs acting on viscera Chemotherapeutic agents

Chapter 5 Intrduction to Pharmacologyof Efferent Nervous System

Zhang BinInstitute of Pharmacology

School of MedicineShandong University

Organization of Nervous system

efferent nervous system (ENS)

autonomic nervous system (vegetative nervous system)

somatic motor nervous system

Efferent neurons of the autonomic nervous system

Classification of ENS according to the released neurotransmitters

cholinergic nerve: acetylcholine (Ach)

noradrenergic nerve: noradrenaline ( NA)

Classification of ENS

Parasympathetic nerve

Cen

tral nervou

s system

Ach skeletal muscle

Ach NA

Ach Ach sweat glands

Ach Ach

Ach adrenal medulla

somatic motor nerve

sympathetic nerve

glands, smooth muscle, heart

heart, vessel,smooth muscle

Section 1 Neurotransmitter and Receptor of ENS

Neurotransmitter of ENS

The receptors of ENS

一 . Neurotransmitter of ENS1.Development of neurotransmitter theory 100 years ago Chemical transmission

electronic transmission 1946 Von Euler NA (noradrenaline) 1921 loewi double frog heart experiment 1926 Dale Ach (acetylcholine)

2.Biosynthesis, storage, release and termination of neurotransmitters

Ach (acetylcholine) NA (noradrenaline)

inhibitor

2.Biosynthesis, storage, release and termination of neurotransmitters

(1)Biosynthesis

choline + acetyl coenzymeA Ach

tyrosine dopa DA NA

choline acetylase

TH DD DH

(2) Storage

+ATP+protein store in vesicles

Ach

NA

(3)release

exocytosis quantal realease cotransmission

(4)Termination

Ach: acetylcholinesterase (AchE)

in synapse NA: uptake1 (neuronal uptake ) 75%-90%

storage in vesicles\ MAO

uptake2(non-neuronal uptake)

COMT\MAO

二 . The receptors of ENS

Classification, Distribution and Effect

Choline receptors (Cholinoceptors )

M-R: muscarine N-R: nicotine

Cholinoceptors

M-R: M1-R: ganglion, CNS

M2-R: heart, presynaptic sites (negative

feedback), CNS M3-R: exocrine glands, smooth muscle,

endothelium, CNS M4 –R: exocrine glands, smooth muscle, CNS

M5 -R: CNS

Cholinoceptors

N-R: nicotine

NM-R: skeletal muscle

NN-R: ganglion and CNS

adrenoceptor: NA AD

α-R α1-R:

postsynaptic effector cells

(especially smooth muscle)

α2-R:

presynaptic nerve terminals (negative feedback),

platelet, smooth muscle, lipocytes

adrenoceptor

β-R β1-R: postsynaptic effector cells,

(especially heart, lipocytes,)

presynaptic nerve terminals β2-R: postsynaptic effector cells,

(especially smooth muscle) β3-R: postsynaptic effector cells,

(especially lipocytes)

Classification of receptor according to their structure

G-protein-coupled receptor: -R, -R, M-R, DA-R, 5-HT-R Ligand-gated receptors N-R

Structure of G-protein-coupled Receptor

Molecular Mechanism of Gq-protein-coupled Receptor

Molecular Mechanism of Gi/s-protein-coupled Receptor

Structure of ligand-gated ion channel Receptor

Molecular Mechanism of ligand-gated ion channel receptor

1. Cholinoceptors M-R: G-protein-coupled receptor

M1-R:Gq-protein-coupled receptor

M2-R-Gi-protein-coupled receptor N-R: ligand-gated ion channel receptor 2. adrenoceptor: G-protein-coupled receptor

α1 –R :Gq-protein-coupled receptor

α2 –R: Gi-protein-coupled receptor β-R :Gs-protein-coupled receptor

Molecular Mechanism of Receptor

N-R Na +, K+, Ca2+

G-p

rotein-cou

pled

receptor

ligand-gated receptor :

(-) PKA

cAMP

M1-R

M2-R

Gq

Gi

K+, Ca2+

(-) AC cAMP

PLC IP3

DAG

α1 -R

α2 -R

β-R (+) AC

(-) AC Gi

GqPLC, PLA2, PLD

Gs cAMP

(-) PKA

(+) PKA

Ca2+

(+) PKC

terminology adrenergic adrenergic receptor cholinergic cholinergic receptor postsynaptic receptor presynaptic receptor

Section 2The physiological actions of ENS

Co-innervation and Dominant Theory

Sympathetic actions: fight and flight response Parasympathetic actions: rest and digest response

Section 3 The basic mechanisms of

actions of ENS drugs

1.Direct action of receptors

agonist

blocker (antagonist) 2.lnfluence of neurotransmitters

biosynthesis

release

storage

conversion

Section 4 The classification of the ENS drugs

（三）抗胆碱酯酶药

Chapter 6 parasympathomimetics

Cholinoceptor agonists (cholinomimetics)

Anticholinesterase agents (cholinesterase-inhibiting drugs)

Drugs of enhancers of ACh release

Cholinoceptor Agonists

M-R agonists:

Choline esters: acetylcholine (ACh) alkaloids: pilocarpine N-R agonists:

nicotine

Section 1 M-R agonists

Acetylcholine (ACh)1. unstable

2. low selectivity

3. administration route

[Pharmacological actions]

Directly activate M-R, N-R muscarinic actions: small dose nicotinic actions: large dose

1.muscarinic actions: small dose

1.cardiovascular system vessel dilate

a. NO release↑

(M3 R →EDRF(NO) ↑→GC →cGMP↑→ intracellular Ca2+↓)

b. NA release↓ BP (HR) Heart depress:

negative (chronotropic, dromotropic, inotropic) effect

1.muscarinic actions: small dose

2.glands ↑3.gastrointestinal tract: motility increase, secretion stimulation4. urinary bladder: detrusor muscle (逼尿肌） contraction, trigone and sphincter relaxation5.eye: sphincter muscle of iris ( 虹膜） contract: miosis ciliary muscle contract: near vision

2.nicotinic actions:large dose NN-R: dominant nerve actions

NM -R:skeletal muscle contraction

alkaloids

Pilocarpine （毛果芸香碱，匹鲁卡品） Muscarine （毒蕈碱） Arecoline （槟榔碱 ） Oxotremorine （氧化震颤素）

Pilocarpine

Pharmacological actions: selectively activate M-R

1.Eye miosis : pupiliary sphincter decrease intraocular pressure spasm of accommadation : ciliary muscle

2. Glands secrete increasingly

(sweat gland, salivary gland)

3. Smooth muscle

4. Cardiovascular system

Clinical uses

1.Glaucoma( 青光眼）

angle-closure glaucoma open-angle glaucoma

What is Glaucoma? increased pressure within the eye. Cells inside

the eye produce aqueous humor that maintains the shape of the eye and nourishes the tissues inside the eye. The balance of fluid production and drainage is responsible for maintaining normal pressure within the eye.

In glaucoma, the drain becomes clogged but the eye keeps producing fluid. Therefore, the pressure in the eye increases. The increased pressure in the eye actually can cause the eye to stretch and enlarge

How does Glaucoma affect the eye?

Vision Loss. Pressure damage to the optic nerve and decreased blood flow to the retina, results in loss of vision. However, if the pressure in the eye remains uncontrolled, the retina degenerates and vision is permanently lost. Permanent blindness can occur within several hours if the pressure is very high and the glaucoma develops rapidly

Pain. Humans have normal intraocular pressures between 10 and 20 mmHg. Glaucoma often results in pressures of 20-28 mmHg in humans. The pain persists in the form of a constant headache or migraine. This discomfort can result in decreased activity, less desire to play, irritability, or decreased appetite

2.iritis （虹膜炎）， iridocyclitis （虹膜睫状体炎）3.others :dry mouth

Adverse reactions

Muscarine （毒蕈碱） Amanita muscaria （捕蝇蕈）

Inocybe （丝盖伞菌属）Clitocybe （杯伞菌属）

Section 2 N-R agonists ——nicotine

Nicotine: from tobaccoAction: NM, NN, CNS and dependence (double phase) Tobacco poison: Hypertension, coronary heart disease, cerebrovascular disease, cancer , Atherosclerosis

China:

Largest tobacco productive country,

Largest tobacco consumption country

No smoking ！ Stop smoking ！

Section 3 Anticholinesterase Agents

Cholinesterase:

true Cholinesterase (AChE)

Pseudocholinesterase

Anticholinesterase Agents-----indirect acting cholinomimetics

Classification according to structure

non-covalent bonding agents: Edrophonium chloride ( 依酚氯铵 ): strong polarity, short

tacrine ( 他克林 ): strong lipophilia, long donepezil ( 多奈哌齐 ) : strong lipophilia, long Carboxamide( 氨甲酰类 ): Physostigmine( 毒扁豆碱 ) Pyridostigmine( 吡斯的明 ) Demecarium( 地美溴铵 )

rivastigmine( 利凡斯的明 ) orgnaophosphorus compound( 有机磷化合物 )

亲和力 亲脂性 BBB 维持时间

依酚氯铵 一般 弱 — 短

他克林 较高 强 ＋ 长

多奈哌齐 较高 强 ＋ 长

Classification according to pharmacological property

Reversible Anticholinesterase agents

irreversible Anticholinesterase agents

Mechanisms of actions: Pharmacological actions:

1. eye

2. gastrointestinal tract （ esophagus, stomach, intestine)

3. motor end plate

4. glands

5. cardiovascular system

Clinical Uses 1. Myasthenia gravis ( 重症肌无力 ): NeostigminePyridostigmine( 吡斯的明 )Ambenonium chloride ( 安贝氯胺 )

Clinical Uses

2. Postoperative abdominal distension; Urinary retention: Neostigmine

3. glaucoma: Physostigmine( 毒扁豆碱 )

Demecarium( 地美溴铵 )

4. intoxication of d-tubocurarine: Neostigmine ， Edrophonium chloride ( 依酚氯铵 ):

5. Alzheimer’s disease:

tacrine, donepezil, rivastigmine, galanthamin

6. Supraventricular tachyarrhythmias

Common used agents

Reversible Anticholinesterase agents

Neostigmine( 新斯的明） actions ：1. Inhibit AChE

2. Activate NM-R on motor endplate

3. Strong effect on skeletal muscle

4. Not into CNS

Uses:

1. Myasthenia gravis: Skeletal muscle contraction

po, sc, im iv

2. Postoperative abdominal distension; Urinary retention

3. intoxication of d-tubocurarine and atropine

4. Supraventricular tachyarrhythmias

5. Glaucoma

Adverse reactions: Cholinergic overexcitation (cholinergic crisis) Treatment : atropine d-tubocurarine

Pyridostigmine ( 吡斯的明 ) Weaker than Neostigmine slower than Neostigmine Longer than Neostigmine Not into CNS Used to treat Myasthenia gravis Contraindication: mechanical ileus ， urinary obstruction

Physostigmine

characteristics 1. Stronger than neostigmine 2. Can enter CNS 3. Have no direct action on R

actions ： 1. eye 2. systemic action Uses: 1. Glaucoma 2. Intoxication of anticholine agents: Atropine Tricyclic antidepressant Dibenzothiazine antipsychotics

Comparison to pilocarpine 1. More rapid 2. Stronger 3. longer

Donepezil Rivastigmine Tacrine —— Alzheimer’s disease

Reversible anticholinesterase agents

neostigmine\Pyridostigmine\Ambenonium\Galanthamine: Myasthenia gravis

Physostigmine\Demecarium : Glaucoma Edrophonium chloride: diagnostic test for

myasthenia gravis Donepezil\rivastigmine\Tacrine\:Alzheimer’s

disease

Irreversible Anticholinesterase Agents--Organophosphates

Mechanisms of intoxication Pathway of intoxication signs of acute intoxication 1.M manifestation (muscarinic excess )

2.N manifestation(nicotinic effects)

3.CNS effects Chronic intoxication

Prevention and treatment of organophosphates intoxication

Prevention Treatment of acute intoxication 1.maintenance of vital signs

2.Decontamination to prevent further absorption

3.Symptomatic treatment

1) atropine 2) cholinesterase reactivator

Cholinesterase Reactivators

Pralidoxime iodide(PAM):碘解磷定 Mechanisms of action

therapeutic effect 1. inhibit Nm manifestation——strong 2. inhibit M manifestation——weak 3. CNS

碘解磷定磷酰化AChE

复合物磷酰化碘解磷定

AChE

Pralidoxime chloride (PAM-Cl): 氯解磷定 better water-solubility im and iv little adverse reaction

Chapter 7 cholinoceptor-blocking drugs

M-R blockers N-R blockers: NN-R blockers

NM-R blockers

Muscarinic cholinoceptor -blocking drugs

Atropine and atropine-like alkaloids Synthetic atropine substitutes

atropine-like alkaloids and their resources

植物 主要生物碱 颠茄 (atropa belladonna) 莨菪碱 (hyoscyamine )曼陀罗 (datura stramonium) 莨菪碱洋金花 (datrua sp) 东莨菪碱 (scopolamine)

莨菪 (hyoscyamus niger) 莨菪碱 唐古特莨菪 (scopolia tangutica) 山莨菪碱 (anisodamine) 樟柳碱 (anisodine

颠茄 莨菪

曼陀罗洋金花

Atropine

pharmacological actions:

block M-R

block NN-R in large dose

pharmacological actions

1. glands: secretion↓salivary, sweat> lacrimal, respiratory >gastric acid

, pancreatic, intestinal juice

2. eyes

(1) mydriasis

(2) increase intraocular pressure

(3) paralysis of accommodation

3. splanchnic smooth muscle: relaxation (spasmodic)

GI tract, detrusor muscle of bladder: significant

Bile tract, bronchial, uterine ( 子宫 ): weak

4. heart:

(1)HR Therapeutic dose: decrease (presynaptic M1blockade)

Large dose: increase (block vagal effect on M2 –R)

(2) A-V conduction:

5.vessels: dilation( in large dose)

(1) Direct effect

(2)Compensative reaction by temperature rise

6.CNS: excitation

Organ sensitivity:

Gland ＞ eye ＞ splanchnic smooth muscle ＞ cardiovascular system ＞CNS.

Clinical Uses

1. Anti-smooth muscle spasm2.  Pre-anaesthesia medication agent3.  Ophthalmological use (1) iridocyclitis (2) optometry

(3) examination of retina4. Bradyarrhythmias5. Shock (septic shock ):Cautions

6. Intoxication of organophosphate

adverse reactions

1.Common Side Effects

2. Acute Poisoning

minimal lethal dose: adults – 80~130mg

children-- 10mg

Prevention

1. Decontamination: to prevent further absorption

2. Antidotes: Parasympathomimetics

3. Maintenance of vital signs

contraindictions

Glaucoma prostatic hypertrophy

anisodamine(654-2)山莨菪碱

Characteristic of actions 1.high selectivity(smooth muscle and vessels)

2.little side effect (not pass through BBB)

Uses 1.septic shock

2.visceral colics.

Scopolamine( 东莨菪碱 )

[Characteristics] 1.CNS actions: depression (strong) 2.peripheral actions: glands: strong others: weak Uses: 1.preanaesthesia medication 2. prevention motion sickness 3. Parkinson disease 4. traditional medicine anaesthesia

中药麻醉 华佗（公元 141 ～ 203 年） “ 麻沸散” 曼陀罗 ( 洋金花 ) 徐州医学院附属医院 : 中药麻醉汤 ( 针

剂 ) 东莨菪碱

Section 2 Synthetic atropine substitutes

Synthetic Mydriatics Synthetic Antispasmatics Selective M1 Antagonists

Synthetic Mydriatics

Homatropine( 后马托品 ) Tropicamide( 托吡卡胺 ) Cyclopentolate( 环喷托酯 ) Eucatropine( 尤卡托品 )

Comparison of some mydriatics

drugsconcentration(%)

mydriasis paralysis of accommodation

peak(m) duration(d)

peak(h) duration(d)

atropine 1.0 30~40 7~10 1~3 7~12

homatropine 1.0~2.0 40~60 1~2 0.5~1 1~3

tropicamide 0.5~1.0 20~40 0.25 0.5 <0.25

cyclopentolate 0.5 30~50

1 1 0.25~1

eucatropine 2.0~5.0 30 1/12~1/4

Uses: iridocyclitis

optometry

examination of retina

Synthetic Antispasmatics

Quaternary amines( 季胺类 ) ：

Propantheline bromide( 溴丙胺太林，普鲁本辛 )

1. selective blockade of GI tract :

2. ulceration, GI spasm, bladder stimulation

3. neuromuscular block action: toxic dose

4. low BBB permeability

Quaternary amines( 季胺类 ) ：

Ipratropium bromide( 异丙托溴胺 )

1. Relieve bronchospasm by inhalation

2. Uses: chronic obstructive pulmonary disease, bronchial asthma

3. ganglionic block action stronger than atropine

4. low BBB permeability

Tertiary amines( 叔胺类 ) ： Mydriatics

Anticholinergic in CNS

Antispasmatic agents

Benactyzine ( 贝那替嗪，胃复康）1. Relieve smooth muscle spasm

2. Antianxiety effect

Selective M1 Antagonists

Pirenzepine( 哌仑西平 ) Telenzepine( 替仑西平 ) Inhibit secretion of gastric acid Clinical use: peptic ulcer Not into CNS

受体亚型 分布 效应N1受体

N2受体M1受体

M2受体

M3受体

神经节肾上腺髓质骨骼肌神经节

窦房节房室节心肌平滑肌外分泌腺

神经节除极儿茶酚胺释放骨骼肌收缩介导迟发性兴奋突触后电位延缓自发除极，减慢心率减慢传导速度降低收缩力收缩分泌增多

受体亚型 分布 效应1受体

2受体

1受体2受体

3受体

血管平滑肌生殖道泌尿道平滑肌肝脏小肠平滑肌心脏胰岛细胞血管平滑肌血小板神经末梢心脏肾小球旁器细胞平滑肌肝脏脂肪组织

收缩收缩肝糖原分解松弛增强收缩力减少胰岛素分泌收缩聚集减少去甲肾上腺素释放兴奋增加肾素分泌松弛肝糖原分解脂肪分解