Chapter 6 Introduction to autonomic Pharmacology.ppt

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Section Ⅱ Autonomic Drugs Chapter 6 Introduction to

Autonomic PharmacologyCao Yongxiao 曹永孝

Department of Pharmacology

029-8265 5140; [email protected]

http://pharmacology.xjtu.edu.cn

Autonomic nervous system (ANS) is largely independent on consciousness.vegatable

Anatomy of the Peripheral Nervous SystemThe 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 [email protected]; 029-82655140

The somatic motor nervous system innervates skeletal muscles which receive only one efferent neuron.


precise

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.


There are ganglia between the CNS and the effectors innervated by autonomic nerve system.

Preganglionic fiber, ganglion, postganglionic fiber

Neurotransmitter Chemistry of ANSThe classification of efferent nerves is based on the transmitter--acetylcholine (ACh)or norepinephrine (NE) released from their terminals.

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 [email protected]; 029-

82655140

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.


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 [email protected]; 029-

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Action potential （ AP ） passing down an axon to the axon terminal changes membrane polarization

resulting in Ca2+ 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 [email protected]; 029-

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Cholinergic TransmissionCholine 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).


Cholinergic Transmission

After release, ACh bind to and activate pre- and postsynaptic acetylcholine receptors (cholinoceptor), 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 Ca2+ 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.



.

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

Norepinephrine,NE


.

An action potential causes an influx of Ca2+ 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.


.

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


Another portion of the NE reuptaken into the nerve is deaminated by MAO enzyme.

NE can also activate presynaptic (α2) receptors, to inhibit further release of NE.

膜受体的最大家系膜受体的最大家系

肾上腺素多巴胺肾上腺素多巴胺 5-HT M-5-HT M- 乙酰胆乙酰胆碱多肽类前列腺碱多肽类前列腺素阿片类嘌呤类素阿片类嘌呤类

第二信使第二信使蛋白激酶蛋白激酶 AA 、、 CC 、、GG钙调素依赖蛋白钙调素依赖蛋白DNADNA 依赖蛋白激依赖蛋白激酶酶西安交大医学院药理学系曹永孝 [email protected]; 029-

82655140

Autonomic Receptors G protein-coupled receptor

Receptor: The receptive substances (protein) of a cell that specifically bind, interact with ligands, and transmit information.

Receptors of autonomic nerve system include cholinoceptors, adrenoceptors and dopamine receptors

1 Cholinoceptors :The receptors combined with ACh are classified

as muscarinic and nicotinic receptors.


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2 Adrenoceptors: The receptors combined with NE and adrenaline

include two groups



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-adrenoceptors, β-adrenoceptors and induce respective effects.


(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


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 β1 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。 β2 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 β2 效应：正反馈调节去甲肾上腺素释放。 β3 受体：主要分布在脂肪细胞，多数 β 受体阻断药不能阻断 β3 受体 β4 受体：亦主要分布在心脏，尚无选择性激动药和阻断药。


2) β1 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) β3 effects lipolysis of fat cells. metabolic



2. M effects: 1) Inhibiting heart (M2) 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 (M3) of salivary, respiratory and gastrointestinal tract glands 5) Eye (M3): miosis. near vision.

3. Dopamine receptors 多巴胺受体

Dl 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D2 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.

Dl 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.


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 N1 receptor blocker: hexamethonium N2 receptor blocker: tubocurarine adrenoceptor antagonist drugs

αreceptor blocker: phentolamine α1 receptor blocker: prazosin β receptor blocker: propranolol αandβreceptor blocker: labetolol

2. Influencing transmitters1) 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 BPAdrenergics: Ephedrine releasing NE

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Chapter 6 Introduction to autonomic Pharmacology.ppt