Pharmacology for Autonomic Drugs Shi-Hong Zhang (张世红), PhD Dept Pharmacology for Autonomic Drugs Shi-Hong Zhang (张世红), PhD Dept. of Pharmacology, School of Medicine, Zhejiang University shzhang713@zju.edu.cn

Organization of the nervous system Nervous System Peripheral Nervous System (PNS) Central Nervous System (CNS) Organization of the nervous system

Peripheral Nervous System (PNS) Efferent Division Afferent Division Autonomic System (ANS) Somatic System Parasympathetic Sympathetic Enteric

交感中枢：脊髓胸腰段灰质侧角+迷走神经脑干核团 副交感中枢：三叉神经、迷走神经、舌咽神经、舌咽神经的脑部核团

The Enteric Nervous System (+SNS/PSNS) A highly simplified diagram of the intestinal wall and some of the circuitry of the enteric nervous system (ENS). The ENS receives input from both the sympathetic and the parasympathetic systems and sends afferent impulses to sympathetic ganglia and to the central nervous system. Many transmitter or neuromodulator substances have been identified in the ENS; see Table 6–1. ACh, acetylcholine; AC, absorptive cell; CM, circular muscle layer; EC, enterochromaffin cell; EN, excitatory neuron; EPAN, extrinsic primary afferent neuron; 5HT, serotonin; IN, inhibitory neuron; IPAN, intrinsic primary afferent neuron; LM, longitudinal muscle layer; MP, myenteric plexus; NE, norepinephrine; NP, neuropeptides; SC, secretory cell; SMP, submucosal plexus. The Enteric Nervous System (+SNS/PSNS)

The release of noradrenalin has the following effects: stimulates heartbeat raises blood pressure dilates the pupils dilates the trachea and bronchi stimulates the conversion of liver glycogen into glucose shunts blood away from the skin and viscera to the skeletal muscles, brain, and heart inhibits peristalsis in the gastrointestinal (GI) tract inhibits contraction of the bladder and rectum

Parasympathetic stimulation causes: slowing down of the heartbeat lowering of blood pressure constriction of the pupils increased blood flow to the skin and viscera peristalsis （蠕动）of the GI tract

Sympathetic Nervous System Peripheral Nervous System (PNS) Central System (CNS) Efferent Division Afferent Autonomic System (ANS) Somatic System Parasympathetic Enteric Drugs that produce their primary therapeutic effect by mimicking or altering the functions of autonomic nervous system are called autonomic drugs. Organization of the nervous system

Neurotransmitters Synthesis Storage Release Degradation Receptors Activation

Drug actions and classification Autonomic drugs: mimetics and antagonists (1) Mimetics - direct-acting: receptor agonists - indirect-acting: increasing amounts and/or effects of transmitters (2) Antagonists - direct-acting: receptor antagonists - indirect-acting: decreasing amounts and/or effects of transmitters

Cholinergic Pharmacology Adrenergic Pharmacology

CASE STUDY In mid-afternoon, a coworker brings 43-year-old JM to the emergency department because he is unable to continue picking vegetables. His gait is unsteady and he walks with support from his colleague. JM has difficulty speaking and swallowing, his vision is blurred, and his eyes are filled with tears. His coworker notes that JM was working in a field that had been sprayed early in the morning with a material that had the odor of sulfur. Within 3 hours after starting his work, JM complained of tightness in his chest that made breathing difficult, and he called for help before becoming disoriented.

Cholinergic Terminal Choline Uptake→ ACh Synthesis ACh Storage Choline + AcCoA → ACh ChAT ACh Storage ACh Release ACh Effects - Postsynaptic - Presynaptic ACh inactivation ACh → Choline + Acetate AChE

Acetylcholine Release Regulation - by autoreceptors ACh acting on presynaptic m2-cholinergic receptors - by heteroreceptors NE acting on presynaptic alpha2-adrenergic receptors - by metabolism (extraneuronal) 乙酰胆碱激活M受体，抑制邻近交感神经末梢去甲肾上腺素的释放；而乙酰胆碱的释放也可被突触前α受体所抑制。

Cholinesterases Acetylcholinesterase is located at cholinergic synapses and in erythrocytes (does not hydrolyze succinylcholine) Pseudocholinesterase (synonyms: plasmacholinesterase or butyrylcholinesterase丁酰胆碱脂酶 ) occurs mainly in plasma, liver and in glia (hydrolyzes succinylcholine)

Cholinergic Receptors Muscarinic receptors (M receptors) M1, 3, 5 (smooth muscles); M2, 4(heart) G-protein Coupled End Organs Nicotinic receptors (N receptors) NN (N1) receptors; NM(N2 ) receptors Ligand-gated Ion Channels NMJ & Ganglia

M receptors : G-protein Coupled Muscarinic Receptor Signaling Pathways 平滑肌：M1,3,5 心肌：M2//4

M receptors: Depression of the heart (heart rate, conduction) Contraction of smooth muscles (sensitive: GI tract, bronchial, urinary bladder; insensitive: uterine, blood vascular) Exocrine glands (sensitive: sweat, tears, salivary; insensitive: GI tract); Eye (contraction of sphincter muscle of iris: miosis; contraction of ciliary muscle: contraction for near vision)

Cholinergic Vasodilation The response of an isolated blood vessel to ACh depends on whether the endothelium is intact (unrubbed) or missing When the endothelium is present, ACh causes smooth muscle relaxation by stimulating the production of nitric oxide (NO) in the endothelium In the absence of the endothelium, a small amount of vasoconstriction is observed

N receptors NN receptors（ N1 receptors ） NM receptors （N2 receptors ） - Sympathetic and parasympathetic ganglia - Adrenal medulla NM receptors （N2 receptors ） - The Neuromuscular Junction (NMJ) (Contraction of skeletal muscles)

N receptors : Ligand-gated Ion Channels At the NMJ, N receptors Pentameric with four types of subunits, two a subunits bind ACh for ligand gating All other nAChRs, including those at the peripheral ganglia, have 2 a’s and 3 b’s

Ganglionic Neurotransmission N = Nicotinic AChR M = Muscarinic AChR EPSP = Excitatory Postsynaptic Potential IPSP = Inhibitory Postsynaptic Potential

The Neuromuscular Junction (NMJ) B

Myasthenia Gravis This means “serious disorder the NMJ” This is an autoimmune disease Antibodies against the a subunit of the nAChR The ability of ACh to activate the nAChRs is blocked by the antibodies As for many autoimmune diseases, stress can make the symptoms worse Treatment is to potentiate cholinergic signaling and to remove the antibodies (blood dialysis)

Drug classification 1. Cholinomimetics (1) Direct-acting drugs: Cholinoceptor agonists M, N receptor agonists: acetylcholine M receptor agonists: pilocarpine N receptor agonists: nicotine (2) Indirect-acting drugs: Cholinesterase inhibitors (Anticholinesterases) Reversible: neostigmine Irreversible: organophosphates Cholinesterase reactivators: pralidoxime iodide

Drug classification 2 Cholinergic antagonists (1) Cholinoceptor antagonists M cholinoceptor antagonists atropine (Antimuscarinic drugs) N cholinoceptor antagonists NN cholinoceptor antagonists: mecamylamine (Ganglionic blocking drugs, rarely used) NM cholinoceptor antagonists: succinylcholine (Neuromuscular blocking drugs ) (2) Botulinum Toxin (blocks ACh release)

Cholinomimetics Direct-acting drugs Ach derivatives （胆碱酯类） Natural Muscarinic agonists (生物碱类M受体激动剂) N受体激动剂

Bond cleaved by AChE 乙酰胆碱 卡巴胆碱 醋甲胆碱 氯贝胆碱 AChE resistant

ACh Derivatives Bethanechol is most commonly used, particularly post-op for the treatment of paralytic ileus and urinary retention

Natural Muscarinic Agonists 毒蕈碱 槟榔碱 毛果芸香碱 (Most to least nicotinic) Muscarine: amanita muscaria (mushroom) Pilocarpine: pilocarpus (S. Amer. shrub) Arecoline: areca or betal nuts (India,E. Indies)

“Food” Poisoning Poisoning causes muscarinic overstimulation： - salivation, lacrimation, visual disturbances; - abdominal colic and diarrhea - bronchospasm and bradycardia - hypotension; shock Treatment is with atropine Amanita muscaria 伞形毒蕈 Atropa belladonna 颠茄

Pilocarpine (1) Eyes Miosis: contraction of sphincter muscle of iris Lowing intraocular pressure: enlarging angle of anterior chamber, increasing drainage of aqueous humor Spasm of accommodation: contraction of ciliary muscle, contraction for near vision Ophthalmological uses Glaucoma: narrow (closed)- or wide (open)-angles used for the emergency lowering of intraocular pressure Iritis: miotics缩瞳药/mydriatics扩瞳药

Circulation of aqueous humor

atropine pilocarpine Ciliary muscle (dilation) paralysis of accommodation Canal of Schlemm mydriasis zonule Posterior chamber Anterior chamber far sight lens atropine spasm of accommodation iris miosis zonule Anterior chamber near sight Ciliary muscle (contraction) pilocarpine

Glaucoma Disease of the aging eye - increased intraocular pressure, degeneration of the optic head, and restricted visual field typify primary open-angle glaucoma Obstruction of the aqueous drainage leads to elevated intraocular pressure (IOP), and may result in glaucomatous damage to the optic nerve

Glaucoma Glaucoma management involves lowering IOP by - Decreasing aqueous production by the ciliary body - Increasing aqueous outflow through the trabecular meshwork and uveal outflow paths

pilocarpine: parasympathomimetics increase aqueous outflow by contraction of the ciliary muscle to increase tone and alignment of the trabecular network

Pilocarpine （2） Promoting secretion of exocrine glands, especially in sweat, salivary and tear glands Systemic use Antidote for atropine poisoning Adverse effects M -like syndrome

N receptor agonists: Nicotine Actions at ganglia, NMJ, brain are complex and frequently unpredictable, because of the variety of neuroeffector sites and because nicotine both stimulates and desensitizes effectors. Periphery: HR, BP,  GI tone & motility CNS: stimulation, tremors, respiration, emetic effects The addictive power of cigarettes is directly related to their nicotine content.

Drug classification 1. Cholinomimetics (1) Direct-acting drugs: Cholinoceptor agonists M, N receptor agonists: acetylcholine M receptor agonists: pilocarpine N receptor agonists: nicotine (2) Indirect-acting drugs: Cholinesterase inhibitors (Anticholinesterases) Reversible: neostigmine Irreversible: organophosphates Cholinesterase reactivators: pralidoxime iodide

Acetylcholinesterase (AChE) Activity

These agents are reversible and are used medically (glaucoma or MG) Cholinomimetics- Indirect Agents: AChE Inhibitors A. Competitive (reversible) B. Carbamates (氨甲酰类slowly reversible) C. Organophosphates (irreversible) 依酚氯铵 新斯的明 neostigmine These agents are irreversible and are used as pesticides or for glaucoma These agents are reversible and are used medically (glaucoma or MG) 毒扁豆碱

Acetylcholinesterase Inhibitors: Reversible Edrophonium Rapidly absorbed; A short duration of action (5-15min); Competitive (reversible) Used in diagnosis of myasthenia gravis. Excess drug may provoke a cholinergic crisis, atropine is the antidote.

Acetylcholinesterase Inhibitors: Carbamates Inhibitory Effects are slowly reversible Representative Drugs neostigmine (quaternary amine) pyridostigmine (quaternary amine) physiostigmine (tertiary amine) quaternary amines effective in periphery only tertiary amines effective in periphery and CNS （fat-soluble）

Neostigmine Pharmacological effects AChE(-), ACh release↑, stimulating NMR stronger effect on skeletal muscles effective on GI tract and urinary bladder more polar and can not enter CNS relatively ineffective on CVS, glands, eye

Neostigmine Clinical uses Myasthenia gravis: symptomatic treatment overdose: cholinergic crisis Paralytic ileus and bladder: post operative abdominal distension and urinary retention Paroxysmal superventricular tachycardia（rarely use） Antidote for tubocurarine (筒箭毒碱) and related drug poisoning Glaucoma 胆碱能危象：大量出汗，大小便失禁，瞳孔缩小，睫状肌痉挛，心动过缓，低血压，肌无力，呼吸困难

Neostigmine Adverse effects Cholinergic effects: muscarinic and nicotinic effects, treated with atropine (muscarinic) Contraindications： mechanical ileus（肠梗阻） urinary obstruction bronchial asthma poisoning of depolarizing skeletal muscle relaxants (e.g. succinylcholine, 琥珀酰胆碱)

Acetylcholinesterase Inhibitors: Irreversible Bond is hydrolyzed in binding to the enzyme 乙磷硫胆碱 梭曼 For ophthalmic use Dichlorvos 敌敌畏 对硫磷 对氧磷 沙林梭曼塔崩：战争毒气 Dimethoate 乐果 马拉硫磷 马拉氧磷

Organophosphates Pralidoxime can restore AChE activity if administered soon after toxin exposure. Conjugating with organophosphate by oxime group; Conjugating with free organophasphates

Organophosphates (1) Toxic symptoms Acute intoxication Muscarinic symptom: eye, exocrine glands, respiration, GI tract, urinary tract, CVS Nicotinic symptoms: NN: elevation of BP, increase of HR; NM: tremor of skeletal muscles CNS symptoms: excitation, convulsion; depression (advanced phase)

Organophosphates (1) Toxic symptoms Chronic intoxication usually occupational poisoning plasma ChE activity ↓, weakness, restlessness, anxiety, tremor, miosis, ……

Organophosphates (2) Detoxication Elimination of poison; Supportive therapy Antidotes Atropine－antagonizing muscarinic effects; early, larger dose, and repeated use Cholinesterase reactivators－reactivation of phosphated AChE; moderate-severe patients, early use (More effective on tremor), combined with atropine Pyraloxime methoiodide (PAM) Pralidoxime chloride: safer than PAM Obidoxime chloride: two active oxime groups

Why isn’t this ACHEI pesticide neurotoxic to humans? Malathion Insects and mammals metabolize the ‘prodrug’ differently Insects - P450 metabolism: P-S bond converted to P-O bond: now, the molecule, malaoxon, is an active inhibitor Mammals – esterase activity: hydrolyzes the molecule into inactive metabolites

Summary: ACHEI Applications Pharmacological Actions: Increases ACh concentrations at cholinergic synapses, thereby increasing cholinergic activity. glaucoma (e.g. physiostigmine毒扁豆碱, echothiophate乙磷硫胆碱 ) myasthenia gravis (e.g. Edrophonium, neostigmine, pyridostigmine ) reverse neuromuscular blockade from competitive antagonists (neostigmine) Alzheimer’s disease (tacrine & donepezil) chemical warfare agents insecticides

Drug classification 2 Cholinergic antagonists (1) Cholinoceptor antagonists M cholinoceptor antagonists atropine (Antimuscarinic drugs) N cholinoceptor antagonists NN cholinoceptor antagonists: mecamylamine (Ganglionic blocking drugs, rarely used) NM cholinoceptor antagonists: succinylcholine (Neuromuscular blocking drugs ) Botulinum Toxin (blocks ACh release)

Muscarinic Antagonists (Antimuscarinic drugs) Tertiary amines（叔铵） Quaternary amines（季铵） 异丙托铵 噻托溴铵

Atropa belladonna Datura stramonium 颠茄 曼陀罗 Datura sp. Henbane Seed 洋金花 山莨菪

Atropine 1. Pharmacological effects (1) Inhibition of exocrine gland secretion salivary, sweat glands tear, respiratory tract glands relatively ineffective: GI tract (2) Eye mydriasis (瞳孔散大) rise in intraocular pressure paralysis of accommodation

atropine pilocarpine Ciliary muscle (dilation) paralysis of accommodation Canal of Schlemm mydriasis zonule Posterior chamber Anterior chamber far sight lens atropine spasm of accommodation iris miosis zonule Anterior chamber near sight Ciliary muscle (contraction) pilocarpine

Atropine 1. Pharmacological effects (3) Antispasmodic action on smooth muscle sensitive: GI, urinary bladder (spasmodic state) relatively insensitive: bile duct, urinary tract, bronchial tract insensitive: uterus

Atropine Pharmacological effects (4) Cardiovascular System: dose dependent Lower therapeutic doses: HR↓(bradycardia); Blood vessels and blood pressure: no effect Moderate to high therapeutic doses / high vagal tone: HR↑ (tachycardia); A-V conduction ↑ Larger doses: cutaneous vasodilatation (5) CNS stimulation sedation, memory loss, psychosis (high dose)

Atropine 2. Clinical uses (1) Ophthalmology Measurement of the refractive errors (屈光不正): children Acute iritis or iridocyclitis: mydriatics/miotics (2) Antispasmodic agent GI, biliary or renal colic, enuresis (3) Inhibiting exocrine gland secretion Preanesthetic medication (4) Bradycardia sinus or nodal bradycardia, A-V block (5) Antidote for organophosphate poisoning

Atropine 3. Adverse effects (1) Side effects dry mouth, blurred vision, “sandy eyes” (2) toxicity Lethal dose: 80~130 mg (adult), 10 mg (child) Low: xerostomia (dry mouth); anhidrosis (Dry skin), tachycardia Moderate: above plus mydriasis, cycloplegia (睫状肌麻痹); difficulty speaking, swallowing & urinating; and hot, red, dry skin High: above plus ataxia, hallucinations & delirium; coma (i.e. CNS symptoms)

Atropine 3. Adverse effects (3) Detoxication Symptomatic treatment: e.g. diazepam. Physostigmine or pilocarpine (4) Contraindications glaucoma, prostatauxe （前列腺肥大）, fever

Scopolamine Actions and clinical uses Peripheral effects are similar to atropine; but has stronger central effects (depression) Pre-anesthetic medication, prevention of motion sickness, Parkinson’s disease

Anisodamine (654-1,2) Actions and clinical uses Peripheral effects, similar to atropine; lower toxicity Septic shock and visceral colic

Other antagonists Propantheline (丙胺太林，普鲁本辛) poor absorption (po) and BBB penetration antispasmodic effects in GI, treatment of peptic ulcer disease Tropicamide (托吡卡胺): mydriatics, cycloplegic shorter duration (1/4 day) Examination of eyes Ipratropium (异丙托铵): asthma Benztropine (苯托品): Parkinson’s disease Pirenzepine (哌仑西平)：M1 selective, peptic ulcer, asthma

CASE STUDY JH, a 63-year-old architect, complains of urinary symptoms to his family physician. He has hypertension and the last 8 years, he has been adequately managed with a thiazide diuretic and an angiotensin-converting enzyme inhibitor. During the same period, JH developed the signs of benign prostatic hypertrophy, which eventually required prostatectomy to relieve symptoms. He now complains that he has an increased urge to urinate as well as urinary frequency, and this has disrupted the pattern of his daily life. What do you suspect is the cause of JH’s problem? What information would you gather to confirm your diagnosis? What treatment steps would you initiate?

Nicotinic receptor antagonists

NN receptor antagonists (Ganglionic blocking drugs) Acting on sympathetic and parasympathetic ganglionic cells; reducing blood pressure by inhibiting sympathetic ganglia ( have been abandoned for clinical use, due to their lack of selectivity) Short-acting; tachyphylaxis (快速抗药反应) Used for treatment of hypertension Trimethaphan(咪噻芬) Mecamylamine (美加明)

NM receptor antagonists (Neuromuscular blocking drugs ) Two classes: Non-depolarizing: drugs act as competitive antagonists Depolarizing: succinylcholine Note: Belong to Skeletal Muscle Relaxants. It is important to realize that muscle relaxation does not ensure unconsciousness, amnesia, or analgesia.

NM receptor antagonists (Neuromuscular blocking drugs ) 1. Depolarizing neuromuscular blockers (Non-competitive) (depolarizing skeletal muscle relaxants) act as acetylcholine (ACh) receptor agonists the depolarized membranes remain depolarized and unresponsive to subsequent impulses (ie, they are in a state of depolarizing block). not metabolized by AChE - diffuse away from the neuromuscular junction and are hydrolyzed in the plasma and liver by pseudocholinesterase (nonspecific cholinesterase, plasma cholinesterase, or butyrylcholinesterase) and elimination by kidney

Succinylcholine (Scoline) acetylcholine succinylcholine Succinylcholine is the only depolarizing agent used clinically (t1/2= 2-4 min). Properties of actions: initially transient fasciculations （肌束震颤） anti-AChE potentiates their effects tachyphylaxis after repeated uses no ganglion-blocking effects at therapeutic doses the drugs are highly polar, poor bioavailability; i.v. as quaternary compounds, do not enter CNS succinylcholine - rapid onset of action (30–60 s) - short duration of action (typically less than 10 min) as succinylcholine enters the circulation, most of it is rapidly metabolized by pseudocholinesterase into succinylmonocholine only a small fraction of the injected dose ever reaches the neuromuscular junction as drug serum levels fall, succinylcholine molecules diffuse away from the neuromuscular junction, limiting the duration of action. Mechanism of Action 1.succinylcholine reacts with the nicotinic receptor to open the channel and cause depolarization of the motor end plate 2.causes an initial depolarization of the muscle membrane, often leading to fasciculations and some muscular contractions prior to inducing paralysis. 3.the depolarized membranes remain depolarized and unresponsive to subsequent impulses (ie, they are in a state of depolarizing block). (recall: excitation-concentration coupling requires end plate repolarization ("repriming") and repetitive firing to maintain muscle tension) 4.With succinylcholine a flaccid paralysis results. 5.succinylcholine has the briefest duration of action of all neuromuscular blocking drugs 6.drug of choice for terminating: laryngospasm, endotracheal intubation electroconvulsive shock therapy

Succinylcholine (Scoline) Main pharmacological effects Transient excitation (fasciculations), and then inhibition (relaxation) Relax Skeletal Muscles in neck, limbs > face, tongue, throat; less effective on breath muscles at therapeutic doses

Succinylcholine (Scoline) Clinical uses An adjuvant in anesthesia or operation Intubation of trachea, esophagus, etc. Prevention of trauma during electroshock therapy （无抽搐电休克疗法） Contraindicated in awake patients, should use under anesthesia

Succinylcholine (Scoline) Adverse effects (1) Apnea (respiratory paralysis) overdose or hypersensitive patients; neostigmine potentiates the toxic effects (2) Muscle spasm muscular pain after operation

Succinylcholine (Scoline) (3) Elevation of K+ in plasma contraindicated in patients with a tendency of hyperkalemia (4) Malignant hyperthermia genetic abnormality, treated by dantrolene (Ca2+ release inhibitor) (5) Others rise in intraocular pressure (glaucoma); histamine release

Genetic Variation: Effects on Duration of Action of Succinylcholine duration of action is prolonged by high doses or by abnormal metabolism. The latter may result from hypothermia (decreases the rate of hydrolysis), low pseudocholinesterase levels, or a genetically aberrant enzyme. Low pseudocholinesterase levels generally produce only modest prolongation of succinylcholine's actions (2-20 min). One in 50 patients has one normal and one abnormal (atypical) pseudocholinesterase gene, resulting in a slightly prolonged block (20-30 min). Even fewer (1 in 3000) patients have two abnormal genes (homozygous atypical) that produce an enzyme with little or no affinity for succinylcholine and have a very long blockade (e.g., 4-8 h) following administration of succinylcholine. Scoline apnea

Succinylcholine (Scoline) Drug interactions - Thiopental （强碱性，可分解scoline） - ChE inhibitors: AChE inhibitors, cyclophosphamide, procaine, etc. - Some antibiotics: kanamycin, polymyxins, etc. (synergism in neuromuscular blocking) Cholinesterase Inhibitors Although cholinesterase inhibitors reverse nondepolarizing paralysis, they markedly prolong a depolarizing phase I block by two mechanisms: - By inhibiting acetylcholinesterase, they lead to a higher ACh concentration at the nerve terminal, which intensifies depolarization. - They also reduce the hydrolysis of succinylcholine by inhibiting pseudocholinesterase.

2. Nondepolarizing neuromuscular blockers (Competitive) (nondepolarizing skeletal muscle relaxants) Tubocurarine (筒箭毒碱) Reversibly bind to the nicotinic receptor at the neuromuscular junction (competitive antagonists) (note: curare rarely used)

Tubocurarine Effects: competitive blockade of NM receptors Uses: adjuvant treatment of anesthesia or operations, eg. tracheal intubation Adverse effects: Respiratory paralysis: can be reversed by neostigmine Enhancing histamine release: BP , bronchoconstriction, salivary secretion Blocking ganglion: BP  Contraindications: myasthenia gravis, bronchial asthma, shock, child (< 10 y) Therapeutic Applications: - to obtain better muscle relaxation in surgical anesthesia. sensation is unaffected and full anesthesia must be maintained. - skeletal muscle relaxation facilitating tracheal intubation

Benzylisoquinolines（苄基异喹啉类） Other nondepolarizing neuromuscular blockers Benzylisoquinolines（苄基异喹啉类） atracurium （阿曲库铵） doxacurium（多撒库铵） mivacurium（米库铵） Ammonio steroids（类固醇铵类） pancuronium （潘库铵） vecuronium（维库铵） pipecuronium（哌库铵） rocuronium（罗库铵）

Botulinum Toxin (肉毒杆菌毒素) Skeletal Muscle Relaxants blocks ACh release from cholinergic terminals selective for ACh terminals - irreversible; Botox acts as a protease that cleaves specific proteins involved in exocytosis, results in flaccid paralysis (松弛性瘫痪) in muscles;

Acts by cleaving SNAP proteins → inhibits ACh release Btx, taken up into vesicles, cleaves the SNARE proteins, preventing assembly of the fusion complex and thus blocking the release of ACh.

Botulinum Toxin an anaerobic bacillus, clostridium botulinum can multiply in preserved food it synthesizes a protein that can be absorbed (pinocytosis or transport?) from the GI tract to reach the systemic circulation penetrates tissues to reach cholinergic nerve terminals then, it is uptaken (pinocytosis) and internalized in vesicles whose lumen becomes acidified - the low pH of the vesicles splits the inactive molecule into 2 active enzymes that have proteolysis functions

Botulinum Toxin Applications • Strabismus (lack of parallelism of eyes), blepharospasm (eyelid spasm), dystonia (abnormal tonicity). • Excessive sweating • Cosmetic procedures ( “frown lines” or “crow’s feet”) Note: effects can last for ~3-6 months.