Chapter 6 Parasympathomimetics Cholinoceptors Agonists Anticholinesterases

Section1. M-R Agonists choline esters: 均含有季铵基团, (M-R, N-R) acetylcholine (Ach)：unstable, low selectivity methacholine (醋甲胆碱) carbachol (卡巴胆碱) bethanechol chloride (氯贝胆碱) alkaloids: (M-R) pilocarpine muscarine arecoline (槟榔碱)

Effective in large dose iv Choline esters Acetylcholine (Ach,乙酰胆碱) [Pharmacological actions] Directly activate M, N-R muscarinic actions: in small dose nicotinic actions: in large dose Effective in large dose iv Local effect by im, sc

横纹肌

1. muscarinic actions (1) cardiovascular system Robert Furchgott 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: mainly in atrium Indirect effect (negative feedback NA release ↓): ventricles

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↓，Ca2+ 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) sphincter relaxation ③ bronchus: contraction

① glands secretion: increasingly ② eyes: (3) others ① glands secretion: increasingly ② eyes: miosis (iris sphincter contraction ) near vision (ciliary muscle contraction)

M1M3 M1 M2 不应期 M3 鼻咽部的

2. nicotinic actions (ganglion, skeletal muscle, adrenal medulla) NN-R: co-innervation and dominant theory adrenaline release NM -R: skeletal muscle contraction

Other choline esters 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

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 Eyes and glands are particularly sensitive to this drug. It is primarily used in ophthalmology Pilocarpine [Pharmacological actions]: selectively activate M-R 1. Eye miosis (pupillae sphincter) decrease intraocular pressure (pupillae sphincter) spasm of accommodation (ciliary muscle) 2. Glands secretion: increase 3. Others

Circular muscle M-R Radial muscle α-R

Clinical uses 1.Glaucoma(青光眼） angle-closure glaucoma open-angle glaucoma 1~2%(若高浓度则可加重), 4~8 h 2.iritis(虹膜炎), iridocyclitis(虹膜睫状体炎) 3.others: dry mouth atropine poision

How does Glaucoma affect the eye? What is Glaucoma? Glaucoma is increased pressure within the eye. Cells inside the eye produce a clear fluid ("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. Increased intraocular pressure is painful. We 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.

Adverse reactions Diarrhea Diaphoresis (出汗) Miosis Nausea Urinary urgency

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 Muscarine 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 捕蝇蕈 杯伞菌属 丝盖伞菌属

Section2 N-R agonists (nicotine, lobeline) 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 Lobeline (洛贝林,山梗菜碱): respiratory center stimulants

Tobacco acute toxicity The fatal dose of nicotine is approximately 40 mg, or 1 drop of the pure liquid. This is the amount of nicotine in two regular cigarettes. Fortunately, most of the nicotine in cigarettes is destroyed by burning or escapes via the “sidestream” smoke. 侧流烟雾

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 药物与AChE牢固结合 [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

[Pharmacological actions] Reversible Anticholinesterase agents [Pharmacological actions] 1. eye: like Pilocarpine 2. gastrointestinal tract (esophagus, stomach, intestine) e.g. Neostigmine can increase the motility (amplitude, frequency and tension)

4. glands secrete increasingly 3. neuromuscular junction of skeletal muscle (anti-AChE, neostigmine--excite receptor) 4. glands secrete increasingly 5. 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、新斯的明） 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.

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

Reversible Anticholinesterase agents Neostigmine (新斯的明） (Not into CNS) Skelatal muscle > GI、bladder smooth muscle > CV, glands, eyes, brachial smooth muscle [Clinical Uses] po, sc, im 1. Myasthenia gravis: direct and indirect effects 2. Postoperative abdominal distension; Urinary retention 3. Intoxication of d-tubocurarine and atropine 4. Supraventricular tachyarrhythmias 5. glaucoma Cautions: Cholinergic Crisis (atropine, d-tubocurarine)

Physostigmine (毒扁豆碱 ) Eyes: similar to pilocarpine (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 ) Neostigmine 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） 东京地铁毒气案1995年奥姆真理教 Pathway of intoxication

Mechanisms of intoxication aging

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 复杂的自主神经综合效应 呼吸中枢抑制，血管运动中枢抑制

尿失禁 呼吸困难 肌阵挛 肌纤维自发性收缩

[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 (美曲膦酯,敌百虫) (敌敌畏) 2% NaHCO3, or 1% brine → MgSO4 !! Dipterex―――――→DDVP (美曲膦酯,敌百虫) (敌敌畏) ×NaHCO3

Cholinesterase Reactivators Pralidoxime chloride (PAM-Cl):氯解磷定 Mechanisms of action 磷酰化氯解磷定 氯解磷定 1. 复合物 磷酰化AChE AChE 2. Direct binding with free organophosphates therapeutic effect 1. inhibit Nm manifestation — strong 2. inhibit M manifestation — weak 3. CNS — effective

PAM-Cl also have the followings: better water-solubility and stability different effects on different organophosphate little adverse reaction im, iv

Summary