chapter 6 parasympathomimetics cholinoceptor agonists anticholinesterases

Chapter 6 Parasympathomimetics

Cholinoceptor AgonistsAnticholinesterases

Section1. M-R Agonists

choline esters: 均含有季铵基团 acetylcholine (Ach) ： unstable, low selectivity methacholine (醋甲胆碱 ) carbachol (卡巴胆碱 ) bethanechol chloride (氯贝胆碱 ) alkaloids: pilocarpine muscarine arecoline (槟榔碱 )

[Pharmacological actions]

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

Acetylcholine (Ach, 乙 酰 胆碱 )

Effective in large dose iv

Local effect by im, sc

Choline esters

1. muscarinic actions

(1) cardiovascular system vessel dilation, BP↓ (reflective HR↑) HR a. NO release↑

(M3 R →EDRF(NO) ↑→GC →cGMP↑→ intracellular Ca2+↓) b. NA release↓ Heart depression: atrium>ventricles negative (chronotropic, dromotropic, inotropic) effect

Direct effect

Negative feedback NA release ↓

Robert Furchgott

mechanism of negative chronotropic effect ↓Ca2+ →↓automatic depolarization

mechanism of negative dromotropic effect ↑ ERP of Atrioventricular node & Purkinje fibers

→↓conduction

mechanism of negative inotropic effect atrium: ↑ K+ efflux→ ↑ repolarization → action

potential duration ↓ , ERP↓ ventricles: presynaptic membrane M-R →NA

release↓

(2) splanchnic smooth muscle

① gastrointestinal tract: excitation motility increase; secretion stimulation

② urinary bladder: detrusor(逼尿肌 ) contraction trigone(三角区 )and sphincter relaxation

③ bronchus: contraction

(3) others

① glands secretion: increasingly

② eyes:

miosis (iris sphincter contraction )

near vision (ciliary muscle contraction)

2. nicotinic actions

(ganglion, skeletal muscle, adrenal medulla) NN-R: co-innervation and dominant theory

adrenaline release NM -R: skeletal muscle contraction

Carbachol ( 卡巴胆碱 ): only used in glaucoma Methacholine ( 醋甲胆碱 ): xerosis of oral mucosa ( 口腔粘膜干燥症 )

Bethanechol ( 氯贝胆碱 ): abdominal distension, urinary retention

Other choline esters

Alkaloids

Pilocarpine （毛果芸香碱，匹鲁卡品）

Muscarine （毒蕈碱） Arecoline （槟榔碱） Oxotremorine （震颤素）

natural

synthetic

Pilocarpine

[Pharmacological actions]: selectively activate M-R

1. Eye miosis (pupiliary sphincter) decrease intraocular pressure spasm of accommodation (ciliary muscle)

2. Glands secretion: increase

3. Others

Eyes and glands are particularly sensitive to this drug. It is primarily used in ophthalmology

Circular muscle

M-R

Radial muscle

α-R

Clinical uses

1.Glaucoma( 青光眼） angle-closure glaucoma

open-angle glaucoma

1~2%, 4~8 h

2.iritis( 虹膜炎 ),

iridocyclitis( 虹膜睫状体炎 )

3.others: dry mouth

atropine poision

Adverse reactions

Diarrhea Diaphoresis ( 出

汗 ) Miosis Nausea Urinary urgency

Muscarine

丝盖伞菌属

杯伞菌属

捕蝇蕈

流涎、流泪、恶心、呕吐、头痛、视觉障碍、腹部绞痛、腹泻、支气管痉挛、心动过缓和血压下降、休克

Section2 N-R agonists (nicotine, lobeline)

Lobeline (洛贝林 ,山梗菜碱 ): respiratory center

stimulants

Nicotine ： from tobacco

Action: NM, NN, CNS and dependence

(double phase: agonist and antagonist) Tobacco poison:

Hypertension, Coronary heart disease, cancer,

Cerebrovascular disease, Atherosclerosis, Peptic Ulcers

Section 3 Anticholinesterase Agents

Cholinesterase (ChE) Common properties of anticholinesterase

agents Reversible Anticholinesterase agents Irreversible Anticholinesterase agents

Cholinesterase （ ChE ） True Cholinesterase (acetylcholinesterase, AChE)

(10 5 Ach / min )

Pseudocholinesterase (butyrylcholinesterase, BChE)

Common properties of anticholinesterase agents

[Classifications] chemical structure

non-covalent bonding agents: 依酚氯铵、他克林、多奈哌齐 carboxamide( 氨甲酰类 ): 毒扁豆碱、比斯的明、地美溴铵、利凡斯的明

Organophosphates properties

Reversible Anticholinesterase agents Irreversible Anticholinesterase agents

药物与 AChE 形成的复合物水解速度慢

[Pharmacological actions]

1. eye: like Pilocarpine

2. gastrointestinal tract

(esophagus, stomach, intestine)

e.g. Neostigmine can increase the motility

(amplitude, frequency and tension)

3. neuromuscular junction of skeletal muscle (anti-AChE, neostigmine--excite receptor)

4. glands secrete increasingly5. others (urinary tract, bronchia,

cardiovascular system)

Dominant theory, mainly negative effect

[Clinical Uses] 1. Myasthenia gravis ( 重症肌无力 )

2. Postoperative abdominal distension; Urinary retention (! no mechanical obstruction )

3.Glaucoma （毒扁豆碱、地美溴铵） 4. Intoxication of d-tubocurarine and cholinoceptor-

blockers 5. Alzheimer’s disease 6. Supraventricular tachyarrhythmias

Myasthenia gravis

A disease affecting skeletal muscle

neuromuscular junctions. Frequent

symptoms are ptosis( 上睑下垂 ),

diplopia( 复视 ), difficulty in

speaking and swallowing, and

extremity weakness. Severe disease

may affect all the muscles, including

those necessary for respiration.

NeostigminePyridostigmine ( 吡斯的明 )Ambenonium chloride ( 安贝氯胺 )Galanthamin ( 加兰他敏 )

Reversible Anticholinesterase agents

Neostigmine ( 新斯的明） Skelatal muscle > GI 、 bladder smooth muscle > CV 、 Glands 、

eyes 、 brachial smooth muscle

[Clinical Uses] po, sc, im (Not into CNS)

1. Myasthenia gravis: direct and indirect effects2. Postoperative abdominal distension; Urinary retention 3. Intoxication of d-tubocurarine and atropine 4. Supraventricular tachyarrhythmias5. glaucoma Cautions: Cholinergic Crisis (atropine, d-tubocurarine)

Physostigmine ( 毒扁豆碱 )

Eyes: similar to pilocarpine (but more rapid, stronger and longer)

Peripheral effects: similar to neostigmine but stronger

Central effects: excitation→inhibition

Clinical use:

1. Glaucoma

2. Intoxication of central anticholinergics (tricyclic antidepressant, antihistaminics, anti-emetic,

antiparkinson agents, phenothiazines antipsychotic agents)

毒性大，除解毒外一般不全身应用

Other Reversible Anticholinesterase agents

1.Myasthenia gravis : neostigmine

Pyridostigmine （吡斯的明） Ambenonium chloride （安贝氯铵 ） Galanthamine （加兰他敏 ）2.Glaucoma: Physostigmine (1~2d)

Demecarium bromide ( 地美溴铵 , 9d )

3.Alzheimer’s disease :

Donepezil( 多奈哌齐 ), Rivastigmine, Tacrine

4.Diagnostic test for myasthenia gravis :

Edrophonium chloride （依酚氯铵，腾喜龙）

Edrophonium chloride 用于诊断重症肌无力和鉴别肌无力危象及胆碱能危象。也用作筒箭毒碱等非去极化肌松剂的拮抗剂。

【用法及用量】①腾喜龙试验 : iv 10mg，注射后重症肌无力症状明显缓解，10分钟后恢复原状，可确定诊断。

②肌无力危象和胆碱能危象的鉴别 : 先注射 2mg，若症状好转，再将其余 8mg注射完，诊断为肌无力危象；若注射2mg后症状加重，应立即停注，诊断为胆碱能危象。

③筒箭毒碱等非去极化肌松弛剂的拮抗剂 : 静脉注射 5 ～10mg/次，总剂量可达 40mg。

Irreversible Anticholinesterase Agents—Organophosphates （有机磷酸酯类）

1 ）弱：敌百虫、乐果、马拉硫磷 2 ）强：敌敌畏 3 ）剧：内吸磷、甲拌磷、对硫磷 4 ）强剧：沙林、塔朋、梭曼 （战争化学毒气）

Pathway of intoxication

aging

Mechanisms of intoxication

Signs of intoxication

1. Acute intoxication: acute cholinergic crisis

(1) M manifestation (muscarinic effects )

(2) N manifestation (nicotinic effects)

(3) CNS effects

2. Chronic intoxication

心率减慢、血压下降、缩瞳可不明显

[signs of acute intoxication] 1.Mild intoxication: M signs

2.Moderate intoxication: M+N signs

3.Severe intoxication: M+N +CNS sign

Prevention and treatment of intoxication

Diagnosis: exposure, symptoms, AChE activity Prevention: important Treatment of acute intoxication 1. Decontamination: to prevent further absorption (gas mask, removal of clothing, gastric lavage) 2. Symptomatic treatment and antidotes (1) Atropine: atropinization ( 阿托品化 ) (2) Cholinesterase Reactivators 3. Maintenance of vital signs

gastric lavage

2% NaHCO3, or 1% brine → MgSO4 !! Dipterex―――――→DDVP

( 敌百虫 ) ( 敌敌畏 )

×NaHCO3

Pralidoxime chloride (PAM-Cl):氯解磷定 Mechanisms of action

磷酰化 AChE

氯解磷定复合物

磷酰化氯解磷定

AChE

Cholinesterase Reactivators

Direct binding with free organophosphates

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

1.

2.

PAM-Cl also have the followings:

better water-solubility and stability

little adverse reaction

im, iv