1 Section Ⅱ Autonomic Drugs Chapter 6 Introduction to Autonomic Pharmacology Cao Yongxiao 曹永孝 Department of Pharmacology ; Autonomic nervous system (ANS) is largely independent on consciousness. vegatable

Anatomy of the Peripheral Nervous System The nervous system is divided into the central nervous system (CNS) and the peripheral nervous system (PNS). The peripheral nervous system (PNS) is further divided into the afferent NS bringing information from the periphery to the CNS and efferent NS carrying signals away from the CNS to the peripheral tissues.

The efferent NS is further divided into the autonomic nervous system (ANS) and somatic motor nervous system 西安交大医学院药理学系 曹永孝

 The somatic motor nervous system innervates skeletal muscles which receive only one efferent neuron. 西安交大医学院药理学系 曹永孝

The ANS is further divided into sympathetic and parasympathetic nervous systems The autonomic nervous system innervates viscera such as heart, smooth muscle, and glands etc. Target tissues receive two types of efferent neurons, sympathetic and parasympathetic nerves. 西安交大医学院药理学系 曹永孝

There are ganglia between the CNS and the effectors innervated by autonomic nerve system. Preganglionic fiber, ganglion, postganglionic fiber

Neurotransmitter Chemistry of ANS The classification of efferent nerves is based on the transmitter--acetylcholine (ACh)or norepinephrine (NE) released from their terminals.efferent nerves 1)Cholinergic fibers: It is fibers releasing ACh 2) noradrenergic fibers: 3) Other fibers: 西安交大医学院药理学系 曹永孝

1) Cholinergic fibers include: somatic motor fibers, preganglionic autonomic fibers, parasympathetic fibers, Cholinergic fibers: It is fibers releasing ACh a few sympathetic postganglionic fibers (controlling sweat gland and blood vessel in skeletal muscle) nervous fibers controlling adrenal medulla. 2) noradrenergic fibers: Most postganglionic sympathetic fibers release norepinephrine. They are noradrenergic fibers. 3) Other fibers: release adrenaline, dopamine and peptides. 西安交大医学院药理学系 曹永孝

Synapse: It is the junction of nerve terminal with the next neuron or effector cell, consisting of presynaptic membrane, postsynaptic membrane and synaptic space. pre post Chemical Transmission in Autonomic NS Transmitter: It is the chemical agent released from nerve terminal that transmits information across synapse and to effectors. Synapse 西安交大医学院药理学系 曹永孝

Action potential （ AP ） passing down an axon to the axon terminal changes membrane polarization resulting in Ca 2+ entry into the cell. This triggers the fusion of vesicles containing neurotransmitters and cell membrane, and causes the release of neurochemical (neurotransmitter) into the synaptic cleft. The transmitters diffuse across the cleft and bind to receptors on the postsynaptic membrane to induce a response in the postsynaptic neuron. Chemical Transmission in synapse 西安交大医学院药理学系 曹永孝

Cholinergic Transmission Choline is transported into the presynaptic nerve terminal by a carrier (A ) Once synthesized, ACh is transported into and packaged in the vesicles. ACh is synthesized from acetyl coenzyme A (Ac-CoA) and choline through the catalytic action of choline acetyl transferase (ChAT). 西安交大医学院药理学系 曹永孝

Cholinergic Transmission After release, ACh bind to and activate pre- and postsynaptic acetylcholine receptors (cholinocept or), showing the action of transmitter. Then, ACh is hydrolyzed rapidly by acetylcholin- esterase (AChE), terminating the action of the transmitter. When an AP reaches the terminal and triggers influx of Ca 2+ which facilitates the fusion of the vesicular membrane with the terminal membrane and results in the release of ACh into synaptic space.

Cholinergic Transmission  Fig. Action potential- induced release of the neurotransmitter acetylcholine (ACh) and its metabolism at the neuromuscular junction. 西安交大医学院药理学系 曹永孝

西安交大医学院药理学系 曹永孝 Tyrosine is transported actively into the noradrenergic ending and is converted to dopa by tyrosine hydroxylase Dopa is decarboxylated to dopamine by dopa decarboxylase. Dopamine is transported into the vesicles and then converted to NE by dopamine-beta- hydroxylase. In the adrenal medulla, NE is further converted to epinephrine. Adrenergic Transmission

西安交大医学院药理学系 曹永孝 An action potential causes an influx of Ca 2+ into the nerve terminal, fusion of the vesicle with the plasma membrane and exocytosis of NE. The transmitter then activates receptors in the postsynaptic membrane.

西安交大医学院药理学系 曹永孝 NE in the synaptic space is actively reuptaken into the nerve and the storage vesicles (uptake l). It is the most important mechanism for termination of the action. NE penetrates into smooth cells ( uptake 2 ) and diffuses away from the receptor site, is inactivated by COMT ( enzyme) to normetanephrine (NMN).

2 ． NA 的合成、释放与灭活：主要在神经末梢合成 合成：酪氨酸从血进人神经元 多巴 多巴胺 NA 贮存：合成的 NA 与 ATP 和嗜铬颗粒蛋白结合贮存于囊泡中。 释放： 神经冲动到达前膜， NA 胞裂外排进入突触 间 隙，与受体结合产 生 效 应 终止： 突触间隙中的 NA 大部分被再摄入神 经末梢囊泡中贮存 ［摄取 1 ］ 少量在非神经组织， 被 COMT 和 MAO 灭活 ［摄取 2 ］ 酪氨酸 羟化酶 多巴 脱羧酶 多巴胺 β- 羟化酶 西安交大医学院药理学系 曹永孝 Another portion of the NE reuptaken into the nerve is deaminated by MAO enzyme. NE can also activate presynaptic ( α 2 ) receptors, to inhibit further release of NE.

膜受体的最大家系 肾上腺素 多巴胺 5-HT M- 乙酰胆碱 多肽类 前列腺素 阿片类 嘌呤类 第二信使 第二信使 蛋白激酶 A 、 C 、 G 钙调素依赖蛋白 DNA 依赖蛋白激酶 西安交大医学院药理学系 曹永孝 Autonomic Receptors G protein-coupled receptor Receptor: The receptive substances (protein) of a cell that specificly bind, interact with ligands, and transmit information. Receptors of autonomic nerve system include cholinoceptors, adrenoceptors and dopamine receptors

1 Cholinoceptors 胆碱受体 : The receptors combined with ACh are classified as muscarinic and nicotinic receptors. 西安交大医学院药理学系 曹永孝

2 Adrenoceptors 肾上腺素受体 : The receptors combined with NE and adrenaline include two groups 西安交大医学院药理学系 曹永孝

Receptor ’ s Function Most of organs are innervated by both of the sympathetic and parasympathetic nervous system. The two systems generally have opposing effects. But, they are uniform in vivo

1) Sympathetic activity Both NE and Ad bind to α-adreno ceptors, β- adreno ceptors and induce respective effects. 西安交大医学院药理学系 曹永孝

(1) Vascular constriction of skin, splanchnic, and mucosa increases blood pressure. (2) Radial muscle of iris contracts to dilate pupil (mydriasis). (3) Contracting sphincters of gastrointestinal tract and urinary bladder. (4) Secretion of sweat glands in palms of hands. (5) Glycogenolysis of liver increase blood sugar. 1. Effects of α 西安交大医学院药理学系 曹永孝

2 ． β 型肾上腺素受体 (β 受体 ) 主要分布在交感神经节后纤维所支配的效应器，再分为 4 种亚型 β 1 受体 ：主要位于心脏、肾小球旁系细胞 选择性激动药为地诺帕明，阻断药为美托洛尔； 效应：心脏兴奋。 β 2 受体 ：主要位于支气管平滑肌、骨骼肌血管和冠状血管、肝脏。 其选择性激动药为特布他林，阻断药为布他沙明； 效应：支气管平滑肌松弛，血管舒张，分解脂糖。 突触前膜 β 2 效应：正反馈调节去甲肾上腺素释放。 β 3 受体：主要分布在脂肪细胞，多数 β 受体阻断药不能阻断 β 3 受体 β 4 受体：亦主要分布在心脏，尚无选择性激动药和阻断药。 西安交大医学院药理学系 曹永孝 ) β 1 effects (1) Cardiac stimulation enhancing the force, rate and conduction of the heart. (2) Renin secretion. 3) β 2 effects (1) Dilatation of artery in skeletal muscles and the heart. (2) Relaxation of bronchus, gastrointestinal and genitourinary smooth muscle. (3) Glycogenolysis and gluconeogenesis of liver. 4) β 3 effects lipolysis of fat cells. metabolic

西安交大医学院药理学系 曹永孝 M effects: 1) Inhibiting heart (M 2 ) to decrease heart rate, conduction and contractility. 2) Vasodilation of artery 3) Contraction of bronchial, gastrointestinal and genitourinary smooth muscles, but relaxation of sphincters 4) Increasing secretion (M 3 ) of salivary, respiratory and gastrointestinal tract glands 5) Eye (M 3 ): miosis. near vision.

3. Dopamine receptors 多巴胺受体 D l 受体： 位于肾、肠系膜、心、脑等血管平滑肌及心肌的多巴胺受体 D 2 受体： 位于交感神经节及突触前膜的多巴胺受体 。 There are 5 subtypes of dopamine receptors. D l receptor is the most important. It locates in vascular smooth muscle cells, brain etc. It can dilate blood vessel, decrease peripheral vascular resistance and increase urinary volume. 西安交大医学院药理学系 曹永孝

Drug Classification of ANS 1. Effects on Receptors 1) Agonist (high intrinsic activity) cholinoceptor-activating drugs M and N receptor agonist: ACh M receptor agonist: Pilocarpine N receptor agonist: Nicotine adrenoceptor-activating drugs αand β receptor agonist: Adrenaline α agonist. NE β agonist: Isoprenaline

2) Antagonist (no intrinsic activity) cholinoceptor-blocking drugs M receptor blocker: atropine N 1 receptor blocker: hexamethonium N 2 receptor blocker: tubocurarine adrenoceptor antagonist drugs αreceptor blocker: phentolamine α 1 receptor blocker: prazosin β receptor blocker: propranolol αandβreceptor blocker: labetolol

2. Influencing transmitters 1) Influencing metabolism of ACh Anticholinesterases: Neostigmine (cholinomimetics) Cholinesterase reactivators: PAM (anticholinergics) 2) Influencing transportation of NE Sympatholytics: Reserpine: inhibit uptake of NE from synapse to vesicles and prevent storage depletion of vesicles release of NE BP Adrenergics: Ephedrine releasing NE