Bài giảng Thuốc tác dụng trên hệ thần kinh thực vật

Figure 3.3Actions of sympathetic and parasympathetic nervous systems on effector organs.Red = sympathetic actionsBlue = parasympathetic actionsEYEContraction of iris radialmuscle pupil d

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THUỐC TÁC DỤNG TRÊN

HỆ THẦN KINH THỰC VẬT

GV: Nguyễn Thùy Dương

Bộ môn Dược lực- Trường ĐH Dược Hà Nội

1

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Tài liệu học tập:

Bộ Y tế (2016), Dược lý học tập 1, NXB Y học

Tài liệu tham khảo:

1 Bertram G Katzung, Susan B Masters, Anthony J Trevor (2012),

Basic and Clinical Pharmacology 12 th Edn., The McGraw-Hill.

2 Laurence L Bruton, Keith L Parker, Donald K Blumenthal, Iain I.O

Buxton (2011), Goodman & Gilman’s Pharmacological Basic of Therapeutics 12 th ed., The McGraw-Hill.

3 Rang H P., Dale M M., Ritter J M., Flower R J (2011), Rang and

Dale's Pharmacology 7th ed, Churchill Livingstone

4 Richard A Harvey, Michelle A Clark, Richard Finkel, Jose A Rey,

Karen Whalen (2012), Lippincott's Illustrated Reviews:

3

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ĐẠI CƯƠNG DƯỢC LÝ DẪN TRUYỀN TRÊN

HỆ THẦN KINH THỰC VẬT

1 Trình bày được định nghĩa, vị trí, cơ chế phân tử

b-adrenergic, muscarinic, nicotinic

2 Phân loại được các thuốc tác dụng trên các hệ

phản ứng của TKTV

!"#$%&'($)*#$%+,

4

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67$168($9#(6$16:%$*;1

Nội dung

• Đặc điểm hệ dẫn truyền trên TKTV

• Chất dẫn truyền thần kinh của TKTV

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!<= >?@A BC DEF GHIJKF GHLF 191*

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Đặc điểm hệ dẫn truyền trên TKTV

7Lippincott’s Illustrated Reviews

Of Pharmacology 5th Ed

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8

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• Đặc điểm của TK giao cảm và phó giao cảm

9

Sợi sau hạch dài

Sợi trước hạch dài Sợi sau hạch ngắn

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10

is also called the craniosacral division Thus, in contrast to the

sym-pathetic system, the preganglionic fi bers are long, and the

postgan-glionic ones are short, with the ganglia close to or within the organ

innervated In most instances there is a one-to-one connection

between the preganglionic and postganglionic neurons, enabling

the discrete response of this division.

5 Enteric neurons: The enteric nervous system is the third division of

the ANS It is a collection of nerve fi bers that innervate the

gastro-intestinal (GI) tract, pancreas, and gallbladder, and it constitutes the

“brain of the gut.” This system functions independently of the CNS

and controls the motility, exocrine and endocrine secretions, and

microcirculation of the GI tract It is modulated by both the

sympa-thetic and parasympasympa-thetic nervous systems.

C Functions of the sympathetic nervous system

Although continually active to some degree (for example, in

maintain-ing the tone of vascular beds), the sympathetic division has the

prop-erty of adjusting in response to stressful situations, such as trauma, fear,

hypoglycemia, cold, and exercise (Figure 3.3)

Figure 3.3

Actions of sympathetic and parasympathetic nervous systems on effector organs.

Red = sympathetic actions

Blue = parasympathetic actions

EYE

Contraction of iris radial

muscle (pupil dilates)

Contraction of iris sphincter

muscle (pupil contracts)

Contraction of ciliary muscle

(lens accommodates for near vision)

TRACHEA AND BRONCHIOLES

Secretion of epinephrine and norepinephrine

URETERS AND BLADDER

Relaxation of detrusor; contraction

of trigone and sphincter

Thick, viscous secretion

Copious, watery secretion

LACRIMAL GLANDS

Stimulation of tears

HEART

Increased rate; increased contractility

Decreased rate; decreased contractility

BLOOD VESSELS

Constriction

(skin, mucous membranes, and

splanchnic area)

Dr Murtadha Al-Shareifi e-Library

Lippincott's Illustrated Reviews: Pharmacology 6thEdn

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• Truyền tin hóa học giữa

các tế bào

– Nội tiết – Tại chỗ – Qua synap

11

signals (neurotransmitters) from the nerve terminals This release is triggered by the arrival of the action potential at the nerve ending,

fusion of the synaptic vesicles with the presynaptic membrane and release of their contents The neurotransmitters rapidly diffuse across the synaptic cleft, or space (synapse), between neurons and combine

with specific receptors on the postsynaptic (target) cell.

1 Membrane receptors: All neurotransmitters, and most hormones

and local mediators, are too hydrophilic to penetrate the lipid ers of target cell plasma membranes Instead, their signal is mediated by binding to specific receptors on the cell surface of target

bilay-organs [Note: A receptor is defined as a recognition site for a stance It has a binding specificity and is coupled to processes

sub-that eventually evoke a response Most receptors are proteins (see Chapter 2).]

2 Types of neurotransmitters: Although over 50 signal molecules in

the nervous system have been identified, norepinephrine (and the closely related epinephrine), acetylcholine, dopamine, serotonin,

involved in the actions of therapeutically useful drugs Each of these chemical signals binds to a specific family of receptors Acetylcholine and norepinephrine are the primary chemical signals in the ANS,

whereas a wide variety of neurotransmitters function in the CNS.

a Acetylcholine: The autonomic nerve fibers can be divided into

two groups based on the type of neurotransmitter released If transmission is mediated by acetylcholine, the neuron is termed cholinergic (Figure 3.8 and Chapters 4 and 5) Acetylcholine mediates the transmission of nerve impulses across autonomic ganglia in both the sympathetic and parasympathetic nervous systems It is the neurotransmitter at the adrenal medulla

Transmission from the autonomic postganglionic nerves to the effector organs in the parasympathetic system, and a few sympathetic system organs, also involves the release of ace-

tylcholine In the somatic nervous system, transmission at the neuromuscular junction (the junction of nerve fibers and volun-

tary muscles) is also cholinergic (Figure 3.8).

b Norepinephrine and epinephrine: When norepinephrine

and epinephrine are the neurotransmitters, the fiber is termed adrenergic (Figure 3.8 and Chapters 6 and 7) In the sympa-

thetic system, norepinephrine mediates the transmission of nerve impulses from autonomic postganglionic nerves to effec-

tor organs [Note: A few sympathetic fibers, such as those involved in sweating, are cholinergic, and, for simplicity, they

are not shown in Figure 3.8.]

IV SIGNAL TRANSDUCTION IN THE EFFECTOR CELL

The binding of chemical signals to receptors activates enzymatic cesses within the cell membrane that ultimately results in a cellu- lar response, such as the phosphorylation of intracellular proteins or

pro-Signaling cell

Gap junction

Target cells Hormone

Nerve

Neuro-transmitter

Target cell

Target cell Blood vessel

Lippincott's Illustrated Reviews: Pharmacology 6thEdn

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168($9#(6$16:%$*;1

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14Lippincott's Illustrated Reviews: Pharmacology 6thEdn

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P?FB GQFR BST UV =BIJ@F BWO =BMG DEF GHIJKF GBXF Y?FB

• Sinh tổng hợp và chuyển hóa catecholamin

– Chuyển hóa: AChE

16

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Sinh tổng hợp, giải phóng và chuyển hóa

các catecholamin

17

• Ức chế

catechol-O-methyltransferase (COMT)

• Ức chế monoamin oxidase (MAO)

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Sinh tổng hợp, giải phóng và chuyển hóa các catecholamin

18

• Norepinephrine transporter (NET) bị ức chế bởi cocain (ngoại vi), thuốc chống trầm cảm 3 vòng (TƯ)

• Vesicular monoamine transporter (VMAT) bị ức chế bởi reserpine

• SNAPs, associated proteins

synaptosome-• VAMPs, vesicle-associated membrane proteins

• Chất k.thích gián tiếp:

tyramin, amphetamin, ephedrin làm tăng gp NE, là

cơ chất của VMAT

CHAPTER 6 Introduction to Autonomic Pharmacology 85

dopamine Several processes in these nerve terminals are potential

sites of drug action One of these, the conversion of tyrosine to

dopa, is the rate-limiting step in catecholamine transmitter

syn-thesis It can be inhibited by the tyrosine analog metyrosine A

high-affinity antiporter for catecholamines located in the wall of

the storage vesicle (vesicular monoamine transporter, VMAT) can be inhibited by the reserpine alkaloids Reserpine causes depletion of transmitter stores Another transporter (norepi-

nephrine transporter, NET) carries norepinephrine and similar

molecules back into the cell cytoplasm from the synaptic cleft

+ VMAT

+

Ca 2+

Calcium channel

Tyrosine

Axon

Nerve terminal

AMPs

SNAPs

Other

Presynaptic receptors

receptor

Hetero-Bretylium, guanethidine

NE

H

NE ATP, P

Tyr

A

Dopamine Dopa

Postsynaptic cell

Diffusion Metyrosine

Adrenoceptors

Autoreceptor

Reserpine

Cocaine, tricyclic antidepressants

Tyrosine hydroxylase

NE, ATP, P

NET

Na

V

receptors

FIGURE 6–4 Schematic diagram of a generalized noradrenergic junction (not to scale) Tyrosine is transported into the noradrenergic ending

or varicosity by a sodium-dependent carrier (A) Tyrosine is converted to dopamine (see Figure 6–5 for details), and transported into the vesicle by

the vesicular monoamine transporter (VMAT), which can be blocked by reserpine The same carrier transports norepinephrine (NE) and several

other amines into these granules Dopamine is converted to NE in the vesicle by dopamine- β-hydroxylase Physiologic release of transmitter occurs

when an action potential opens voltage-sensitive calcium channels and increases intracellular calcium Fusion of vesicles with the surface membrane

results in expulsion of norepinephrine, cotransmitters, and dopamine-β-hydroxylase Release can be blocked by drugs such as guanethidine and

bretylium After release, norepinephrine diffuses out of the cleft or is transported into the cytoplasm of the terminal by the norepinephrine transporter

(NET), which can be blocked by cocaine and tricyclic antidepressants, or into postjunctional or perijunctional cells Regulatory receptors are present

on the presynaptic terminal SNAPs, synaptosome-associated proteins; VAMPs, vesicle-associated membrane proteins

006-Katzung_Ch006_p079-096.indd 85 9/21/11 11:55:19 AM

Basic and Clinical Pharmacology 12th Edn

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Sinh tổng hợp,

dự trữ, giải

phóng và chuyển hóa

Choline

Axon

Nerve terminal

P ostsynaptic cell

ACh ATP, P

VAMPs

SNAPs

Other receptors

Presynaptic receptors

Hemicholiniums

receptor

Hetero-Vesamicol

Acetylcholine autoreceptor

Choline Acetate

Cholinoceptors

Botulinum toxin

ACh

CHT

H+

ACh ATP, P

Vesicles are concentrated on the inner surface of the nerve terminal facing the synapse through the interaction of so-called SNARE proteins on the vesicle (a subgroup of VAMPs called

v-SNAREs, especially synaptobrevin ) and on the inside of the

terminal cell membrane (SNAPs called t-SNAREs, especially

syntaxin and SNAP-25 ) Physiologic release of transmitter from

the vesicles is dependent on extracellular calcium and occurs when

an action potential reaches the terminal and triggers sufficient

19

Katzung BG, Masters SB, Trevor Ạ (2012),

Basic and Clinical Pharmacology 12 th Edn.,

The McGraw-Hill

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• Điều hòa giải phóng chất dẫn

truyền trước synap

– Các receptor tiền synap có thể ức

chế hoặc k.thích giải phóng chất DT

– Ức chế qua autoreceptor tiền synap

xảy ra trên cả sợi noradrenergic và

cholinergic: autoinhibitory feedback

– [A] Có tương tác đồng hình và dị

hình giữa giao cảm và phó giao cảm

– [B] Nhiều chất trung gian khác ảnh

influences on noradrenaline release from sympathetic nerve endings 5-HT, 5-hydroxytryptamine; A, adrenaline; ACh, acetylcholine; NA,

noradrenaline; NO, nitric oxide; PG, prostaglandin; PGE, prostaglandin E.

page 146 page 147

Figure 12.4 Presynaptic regulation of transmitter release from noradrenergic and cholinergic nerve terminals [A] Postulated homotropic and heterotropic interactions between sympathetic and parasympathetic nerves [B] Some of the known inhibitory and facilitatory

influences on noradrenaline release from sympathetic nerve endings 5-HT, 5-hydroxytryptamine; A, adrenaline; ACh, acetylcholine; NA,

noradrenaline; NO, nitric oxide; PG, prostaglandin; PGE, prostaglandin E.

page 146 page 147

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• Hiện tượng đồng dẫn truyền

– Các chất dẫn truyền khác ngoài noradrenaline và acetylcholine (NANC

transmitters) cũng có vai trò trên hệ TKTV: NO, VIP (phó giao cảm),

ATP và NPY (giao cảm), 5-HT, GABA, dopamine

23

Vasoactive intestinal peptide (VIP)

Parasympathetic nerves to salivary glands

Vasodilatation; co-transmitter with acetylcholine

NANC innervation

of airways smooth muscle

Bronchodilatation

releasing hormone

Gonadotrophin-Sympathetic ganglia

Slow depolarisation; transmitter with acetylcholine Substance P Sympathetic

co-ganglia, enteric neurons

Slow depolarisation; transmitter with acetylcholine

co-Calcitonin related peptide

gene-Non-myelinated sensory neurons

Vasodilatation; vascular leakage; neurogenic inflammation

NANC, non-adrenergic non-cholinergic.

Figure 12.6 The main co-transmitters at postganglionic parasympathetic and sympathetic neurons The different mediators generally

give rise to fast, intermediate and slow responses of the target organ ACh, acetylcholine; ATP, adenosine triphosphate; NA, noradrenaline;

NO, nitric oxide; NPY, neuropeptide Y; VIP, vasoactive intestinal peptide.

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24

Figure 12.7 Co-transmission and neuromodulation-some examples [A] Presynaptic inhibition [B] Heterotropic presynaptic inhibition [C]

Postsynaptic synergism ACh, acetylcholine; ATP, adenosine triphosphate; GnRH, gonadotrophin-releasing hormone (luteinising

hormone-releasing hormone); NPY, neuropeptide Y; SP, substance P; VIP, vasoactive intestinal peptide.

As we shall see in subsequent chapters, both membrane and vesicular transporters are targets for various drug effects, and defining the physiological role and pharmacological properties of these molecules is the focus of much current research.

• Hiện tượng đồng dẫn truyền

– Ví dụ

As we shall see in subsequent chapters, both membrane and vesicular transporters are

targets for various drug effects, and defining the physiological role and pharmacological

properties of these molecules is the focus of much current research.

As we shall see in subsequent chapters, both membrane and vesicular transporters are

targets for various drug effects, and defining the physiological role and pharmacological

properties of these molecules is the focus of much current research.

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25

2 Emotions and the ANS: Stimuli that evoke strong feelings, such as

rage, fear, and pleasure, can modify the activities of the ANS

F Innervation by the ANS

1 Dual innervation: Most organs in the body are innervated by both

divisions of the ANS Thus, vagal parasympathetic innervation slows the heart rate, and sympathetic innervation increases the heart rate

Despite this dual innervation, one system usually predominates in controlling the activity of a given organ For example, in the heart, the vagus nerve is the predominant factor for controlling rate This type of antagonism is considered to be dynamic and is fine-tuned at any given time to control homeostatic organ functions The activity

of a system represents integration of influence of both divisions

2 Organs receiving only sympathetic innervation: Although most

tissues receive dual innervation, some effector organs, such as the adrenal medulla, kidney, pilomotor muscles, and sweat glands, receive innervation only from the sympathetic system The control of blood pressure is also mainly a sympathetic activity, with essentially

no participation by the parasympathetic system

G Somatic nervous system

The efferent somatic nervous system differs from the autonomic system

in that a single myelinated motor neuron, originating in the CNS, travels directly to skeletal muscle without the mediation of ganglia As noted earlier, the somatic nervous system is under voluntary control, whereas the autonomic system is involuntary Responses in the somatic division are generally faster than those in the ANS

H Summary of differences between sympathetic, parasympathetic, and motor nerves

Major differences in the anatomical arrangement of neurons lead to variations of the functions in each division (Figure 3.6) The sympathetic nervous system is widely distributed, innervating practically all effec-tor systems in the body In contrast, the parasympathetic division’s dis-tribution is more limited The sympathetic preganglionic fibers have a much broader influence than the parasympathetic fibers and synapse with a larger number of postganglionic fibers This type of organization

Increased blood pressure

Extensive

Length of fibers Location of ganglia Preganglionic fiber branching Distribution Wide Type of response Diffuse

Sites of origin Thoracic and lumbar region of the spinal cord (thoracolumbar)

Within or near effector organs Minimal

Limited Discrete

Brain and sacral area of spinal cord (craniosacral)

PARASYMPATHETIC SYMPATHETIC

Dr Murtadha Al-Shareifi e-Library

1.TÍN HIỆU HƯỚNG TÂM

Từ cảm giác tạng:

-Huyết áp tụt-Giảm áp trên baroceptor ở quai động mạch chủ

- Giảm tần suất xung lực hướng tâm tới tủy (brainstem)

2 ĐÁP ỨNG PHẢN XẠThông qua hệ TKTV gây:

-Ức chế phó giao cảm và hoạt hóa nhánh giao cảm

-Tăng sức cản ngoại biên và lưu lượng tim

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26

change The homeostatic response may be sufficient to reduce the change in mean arterial pressure and to reverse the drug’s effects on heart rate A slow infusion of norepinephrine provides a useful example This agent produces direct effects on both vascular and cardiac muscle It is a powerful vasoconstrictor and, by increasing peripheral vascular resistance, increases mean arterial pressure In the absence of reflex control—in a patient who has had a heart trans-

plant, for example—the drug’s effect on the heart is also stimulatory;

that is, it increases heart rate and contractile force However, in a subject with intact reflexes, the negative feedback response to increased mean arterial pressure causes decreased sympathetic out-

flow to the heart and a powerful increase in parasympathetic (vagus nerve) discharge at the cardiac pacemaker This response is mediated

by increased firing by the baroreceptor nerves of the carotid sinus and the aortic arch Increased baroreceptor activity causes the changes mentioned in central sympathetic and vagal outflow As a result, the

net effect of ordinary pressor doses of norepinephrine in a normal

subject is to produce a marked increase in peripheral vascular

resis-tance, an increase in mean arterial pressure, and a consistent slowing

of heart rate Bradycardia, the reflex compensatory response elicited

by this agent, is the exact opposite of the drug’s direct action; yet it is

completely predictable if the integration of cardiovascular function

by the ANS is understood

Presynaptic Regulation

The principle of negative feedback control is also found at the presynaptic level of autonomic function Important presynaptic feedback inhibitory control mechanisms have been shown to exist

at most nerve endings A well-documented mechanism involves the α 2 receptor located on noradrenergic nerve terminals This receptor is activated by norepinephrine and similar molecules;

activation diminishes further release of norepinephrine from these nerve endings ( Table 6–4 ) The mechanism of this G protein- mediated effect involves inhibition of the inward calcium current that causes vesicular fusion and transmitter release Conversely, a presynaptic β receptor appears to facilitate the release of norepinephrine from some adrenergic neurons Presynaptic receptors

Baroreceptors

Peripheralvascularresistance

Contractileforce

Venoustone

Aldosterone

Bloodvolume

Venousreturn

Strokevolume

Renal bloodflow/pressure

Meanarterialpressure

+

Heartrate

Cardiacoutput

–

Parasympatheticautonomicnervoussystem

+

SympatheticautonomicnervoussystemVASOMOTOR CENTER

FIGURE 6–7 Autonomic and hormonal control of cardiovascular function Note that two feedback loops are present: the autonomic vous system loop and the hormonal loop The sympathetic nervous system directly influences four major variables: peripheral vascular resis-

ner-tance, heart rate, force, and venous tone It also directly modulates renin production (not shown) The parasympathetic nervous system directly influences heart rate In addition to its role in stimulating aldosterone secretion, angiotensin II directly increases peripheral vascular resistance

and facilitates sympathetic effects (not shown) The net feedback effect of each loop is to compensate for changes in arterial blood pressure

Thus, decreased blood pressure due to blood loss would evoke increased sympathetic outflow and renin release Conversely, elevated pressure due to the administration of a vasoconstrictor drug would cause reduced sympathetic outflow, reduced renin release, and increased parasym-

pathetic (vagal) outflow

• Điều hòa chức năng

thông qua TKTV:

Ví dụ trên hệ tim mạch

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27Basic and Clinical Pharmacology 12th Edn

• Điều hòa chức năng thông qua TKTV:

Ví dụ trên mắt

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28

fibers leave the CNS through the thoracic and lumbar spinal nerves

The parasympathetic preganglionic fibers leave the CNS through the cranial nerves (especially the third, seventh, ninth, and tenth) and the third and fourth sacral spinal nerve roots

Most sympathetic preganglionic fibers are short and terminate

in ganglia located in the paravertebral chains that lie on either side

of the spinal column The remaining sympathetic preganglionic

fibers are somewhat longer and terminate in prevertebral ganglia,

which lie in front of the vertebrae, usually on the ventral surface of the aorta From the ganglia, postganglionic sympathetic fibers run

to the tissues innervated Some preganglionic parasympathetic fibers terminate in parasympathetic ganglia located outside the

organs innervated: the ciliary, pterygopalatine, submandibular,

otic, and several pelvic ganglia However, the majority of

para-sympathetic preganglionic fibers terminate on ganglion cells tributed diffusely or in networks in the walls of the innervated

dis-organs Note that the terms “sympathetic” and “parasympathetic”

are anatomic designations and do not depend on the type of mitter chemical released from the nerve endings nor on the kind of effect—excitatory or inhibitory—evoked by nerve activity

In addition to these clearly defined peripheral motor portions

of the ANS, large numbers of afferent fibers run from the ery to integrating centers, including the enteric plexuses in the gut, the autonomic ganglia, and the CNS Many of the sensory pathways that end in the CNS terminate in the integrating centers

periph-of the hypothalamus and medulla and evoke reflex motor activity that is carried to the effector cells by the efferent fibers described previously There is increasing evidence that some of these sensory fibers also have peripheral motor functions

The enteric nervous system (ENS) is a large and highly

orga-nized collection of neurons located in the walls of the tinal (GI) system ( Figure 6–2 ) It is sometimes considered a third

Parasympathetic preganglionic fibers

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

AC, absorp+ve cell;

CM, circular muscle layer;

EC, enterochromaﬃn cell;

EN, excitatory neuron;

EPAN, extrinsic primary

aﬀerent neuron;

IN, inhibitory neuron;

IPAN, intrinsic primary

Trang 29

9#(6$16:%$*;1

Trang 30

80 SECTION II Autonomic Drugs

The nervous system has several properties in common with the

endocrine system, which is the other major system for control of

body function These include high-level integration in the brain,

the ability to influence processes in distant regions of the body,

and extensive use of negative feedback Both systems use

chemi-cals for the transmission of information In the nervous system,

chemical transmission occurs between nerve cells and between

nerve cells and their effector cells Chemical transmission takes

place through the release of small amounts of transmitter

sub-stances from the nerve terminals into the synaptic cleft The

trans-mitter crosses the cleft by diffusion and activates or inhibits the

postsynaptic cell by binding to a specialized receptor molecule In

a few cases, retrograde transmission may occur from the

postsyn-aptic cell to the presynpostsyn-aptic neuron terminal and modify its

sub-sequent activity

By using drugs that mimic or block the actions of chemical

transmitters, we can selectively modify many autonomic functions

These functions involve a variety of effector tissues, including cardiac muscle, smooth muscle, vascular endothelium, exocrine glands, and presynaptic nerve terminals Autonomic drugs are useful in many clinical conditions Unfortunately, a very large number of drugs used for other purposes have unwanted effects on autonomic function (see Case Study)

ANATOMY OF THE AUTONOMIC NERVOUS SYSTEM

The ANS lends itself to division on anatomic grounds into two

major portions: the sympathetic (thoracolumbar) division and the parasympathetic (craniosacral) division ( Figure 6–1 ) Neurons in

both divisions originate in nuclei within the CNS and give rise to preganglionic efferent fibers that exit from the brain stem or spinal cord and terminate in motor ganglia The sympathetic preganglionic

Medulla

D

D1Spinal cord

ACh

ACh ACh

FIGURE 6–1 Schematic diagram comparing some anatomic and neurotransmitter features of autonomic and somatic motor nerves Only

the primary transmitter substances are shown Parasympathetic ganglia are not shown because most are in or near the wall of the organ

innervated Cholinergic nerves are shown in blue; noradrenergic in red; and dopaminergic in green Note that some sympathetic postganglionic

fibers release acetylcholine or dopamine rather than norepinephrine The adrenal medulla, a modified sympathetic ganglion, receives sympathetic

preganglionic fibers and releases epinephrine and norepinephrine into the blood ACh, acetylcholine; D, dopamine; Epi, epinephrine; M,

muscarinic receptors; N, nicotinic receptors; NE, norepinephrine

%<=>$?@A$>BCDEA$FG$BHIHJ>KB$ILM$<N$191* %_= BC TB`F aFR =NO GBXF Y?FB GBb= UcG

Trang 31

CÁC HỆ PHẢN ỨNG CỦA HỆ THẦN KINH THỰC VẬT

HỆ ADRENERGIC

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32

166 Section II / Drugs Acting at Synaptic and Neuroeffector Junctional Sites

The heterogeneity of α adrenergic receptors also is now

appreciated The initial distinction was based on functional and

anatomical considerations when it was realized that

norepineph-rine and other α-adrenergic receptors could profoundly inhibit

the release of norepinephrine from neurons (Westfall, 1977)

(Fig-ure 6–5) Indeed, when sympathetic nerves are stimulated in the

presence of certain α receptor antagonists, the amount of

norepi-nephrine liberated by each nerve impulse increases markedly.

This feedback-inhibitory effect of norepinephrine on its release

from nerve terminals is mediated by α receptors that are

pharma-cologically distinct from the classical postsynaptic α receptors.

Accordingly, these presynaptic α adrenergic receptors were

des-ignated α2, whereas the postsynaptic “excitatory” α receptors

were designated α1 (see Langer, 1997) Compounds such as

clonidine are more potent agonists at α2 than at α1 receptors; by

contrast, phenylephrine and methoxamine selectively activate

postsynaptic α1 receptors Although there is little evidence to

suggest that α1 adrenergic receptors function presynaptically in

the autonomic nervous system, it now is clear that α2 receptors

also are present at postjunctional or nonjunctional sites in several tissues For example, stimulation of postjunctional α2 receptors

in the brain is associated with reduced sympathetic outflow from the CNS and appears to be responsible for a significant compo-

nent of the antihypertensive effect of drugs such as clonidine (see

Chapter 10) Thus, the anatomical concept of prejunctional α2and postjunctional α1 adrenergic receptors has been abandoned in favor of a pharmacological and functional classification (Table 6–6 and 6–8).

Cloning revealed additional heterogeneity of both α1 and α2adrenergic receptors (Bylund, 1992) There are three pharmaco- logically defined α1 receptors (α1A, α1B, and α1D) with distinct sequences and tissue distributions (Tables 6–6 and 6–8) There are also three cloned subtypes of α2 receptors (α2A, α2B, and α2C) (Table 6–8) Distinct patterns of distribution of these subtypes exist.

Owing to the lack of sufficiently subtype-selective ligands, the precise physiological function and therapeutic potential of the subtypes of adrenergic receptors have not been elucidated fully Great

Table 6–6

Characteristics of Subtypes of Adrenergic Receptors*

α1† Epi ≥ NE >> Iso Prazosin Vascular smooth muscle Contraction

Phenylephrine GU smooth muscle Contraction

Liver‡ Glycogenolysis; gluconeogenesis Intestinal smooth muscle Hyperpolarization and relaxation Heart Increased contractile force;

arrhythmias

α2† Epi ≥ NE >> Iso Yohimbine Pancreatic islets ( β cells) Decreased insulin secretion

Clonidine Platelets Aggregation

Nerve terminals Decreased release of NE Vascular smooth muscle Contraction

β1 Iso > Epi = NE Metoprolol Juxtaglomerular cells Increased renin secretion

Dobutamine CGP 20712A Heart Increased force and rate of

traction and AV nodal duction velocity

con-β2 Iso > Epi >> NE ICI 118551 Smooth muscle (vascular,

bronchial, GI, and GU)

Relaxation Terbutaline

Skeletal muscle Glycogenolysis; uptake of K+

Liver‡ Glycogenolysis; gluconeogenesis

β3§ Iso = NE > Epi ICI 118551 Adipose tissue Lipolysis

BRL 37344 CGP 20712A

ABBREVIATIONS: Epi, epinephrine; NE, norepinephrine; Iso, isoproterenol; GI, gastrointestinal; GU, genitourinary. *This table provides examples of drugs that act on adrenergic receptors and of the location of subtypes of adrenergic receptors. †At least three subtypes each of α1 and α2 adrenergic receptors are known, but distinctions in their mechanisms of action have not been clearly defined. ‡In some species (e.g., rat), metabolic responses in

the liver are mediated by α1 adrenergic receptors, whereas in others (e.g., dog) β2 adrenergic receptors are predominantly involved Both types of receptors appear to contribute to responses in human beings. §Metabolic responses in adipocytes and certain other tissues with atypical pharmacological characteristics may be mediated by this subtype of receptor Most β adrenergic receptor antagonists (including propranolol) do not block these responses.

Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11thEdn

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34

168 Section II / Drugs Acting at Synaptic and Neuroeffector Junctional Sites

β 2 Receptors normally are confined to caveolae in cardiac myocyte membranes The activation of PKA by AMP and the importance of compartmentation of components of the cyclic AMP pathway are dis- cussed in Chapter 1.

α Adrenergic Receptors The deduced amino acidsequences from the three α1 receptor genes (α1A, α1B,and α1D) and three α2 receptor genes (α2A, α2B, and

α2C) conform to the well-established GPCR paradigm(Zhong and Minneman, 1999; Bylund, 1992) While not

as thoroughly investigated as β receptors, the generalstructural features and their relation to the functions ofligand binding and G protein activation appear to agreewith those set forth in Chapter 1 and above for the β

receptors Within the membrane-spanning domains, thethree α1 adrenergic receptors share approximately 75%

identity in amino acid residues, as do the three α2

receptors, but the α1 and α2 subtypes are no more lar than are the α and β subtypes (approximately 30% to40%)

simi-α2 Adrenergic Receptors. As shown in Table 6–7, α 2 receptors

couple to a variety of effectors (Aantaa et al., 1995; Bylund,

1992) Inhibition of adenylyl cyclase activity was the first effect observed, but in some systems the enzyme actually is stimulated

by α 2 adrenergic receptors, either by Gi βγ subunits or by weak direct stimulation of Gs The physiological significance of these latter processes is not currently clear α 2 Receptors activate G protein–gated K + channels, resulting in membrane hyperpolarization.

Table 6–8

Subtypes of Adrenergic Receptors

SUBTYPE

GENE LOCATION IN HUMAN CHROMOSOME TISSUE LOCALIZATION SUBTYPE DOMINANT EFFECTS

α1A 8 Heart, liver, cerebellum

cere-bral cortex, prostate, lung, vas deferens, blood vessels

Predominant receptor causing contraction of smooth muscle including vasoconstriction in numerous arteries and veins

Withα1B promotes cardiac growth and structure

α1B 5 Kidney, spleen, lung, cerebral

cortex, blood vessels

Most abundant subtype in heart; with α1A

promotes cardiac growth and structure

α1D 20 Platelets, cerebral cortex,

prostate, hippocampus, aorta, coronary arteries

Predominant receptor causing tion in the aorta and coronary arteries

vasoconstric-α2A 10 Platelets, cerebral cortex,

locus ceruleus, spinal cord, sympathetic neurons; auto-nomic ganglia

Predominant inhibitory autoreceptor in pathetic nerve varicosities

sym-Predominant receptor mediating α2 agonist–

induced antinociception, sedation, hypotension, and hypothermia

α2B 2 Liver, kidney, blood vessels Predominant receptor mediating α2-induced

vasoconstriction

α2C 4 Cerebral cortex Predominant receptor modulating dopamine

neurotransmissionPredominant inhibitory receptor on adrenal medulla

β1 10q240q26 Heart, kidney, adipocytes,

other tissues

Predominant receptor in heart producing + inotropic and chronotropic effects

β2 5q32-q32 Heart; vascular, bronchial,

and GI smooth muscle;

Tiêu đề	Thuốc tác dụng trên hệ thần kinh thực vật
Người hướng dẫn	PTS. Nguyễn Thùy Dương
Trường học	Trường ĐH Dược Hà Nội
Chuyên ngành	Dược lý học
Thể loại	Bài giảng

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