Transcript ACh

Section 3
Drugs Affecting the
Peripheral Nervous System
Hong-guang Nie
Department of Pharmacology
Nervous system
Central Nervous System
Peripheral Nervous System
Efferent Nervous System
Somatic Motor Nervous System
Afferent Nervous System
Autonomic nervous system
Sympathetic Nervous System
Parasympathetic Nervous System
nerve transmitter
乙酰胆碱 (Acetylcholine, ACh)
去甲基肾上腺素 (Norepinophrine, NE)
(Noradrenaline, NA)
Efferent nervous system
Introduction
 Parasympathomimetics
 Cholinoceptor blocking drugs
 Adrenoceptor agonists
 Adrenoceptor blocking drugs

The Peripheral Nervous System


Sympathetic nervous
system has a long
postganglionic connection
Parasympathetic nervous
system has a short
postganglionic connection
NA
ACh
ACh/DA
ACh
ACh
synapse
presynaptic
membrane
 synaptic cleft
 postsynaptic
membrane

乙酰胆碱 (ACh)
synthesized from choline and
acetyl coenzyme A by an
enzyme called choline
acetyltransferase (CAT).
It is stored in small Granules
and released after the arrival
of an action potential.
Degradated by
acetylcholinesterase
(AChE)
去甲基肾
上腺素
(NE)
Cholinergic Receptors 胆碱受体
A. Nicotinic Receptors（烟碱型胆碱受体, N受体）
NM neuromuscular
junction
NN ganglion
axon ending of
presynapic cell
synaptic
vesicle
postsynapic cell
synaptic cleft
receptor for neurotransmitter
neurotransmitter
molecule in
synaptic cleft
receptor for the
neurotransmitter
on postsynapic
cell
ions that affect
membrane
excitability
B. Muscarinic Receptors
（毒蕈碱型胆碱受体， M受体）
Five subtypes:
M1 autonomic ganglion
M2 sinuatrial node, atrium
M3 exocrine gland
M4 exocrine gland
M5
CNS
M1/M5 Stimulate Phospholipase C
Gp
(DAG)
M2 Receptor Regulation of K+/Ca2+ Channels
Adrenergic receptors 肾上腺素受体
A. a receptors （ a型肾上腺素受体）
a1: predominate on smooth muscle of blood
vessels, also on smooth muscle of iris (eye) and
sphincters of GI and urinary tract
a2: predominantly located on presynaptic nerve
terminals modulating nerve activity
B. b receptors （ b型肾上腺素受体）
b1 receptors: are found predominantly in the heart
(SA and AV node, atria & ventricles, His-Purkinje)
activation leads to force of contraction, heart rate;
also cause renin secretion and lipolysis.
b2 receptors: are located on most tissues,
activation leads to relaxation of smooth muscle.
Chapter 17
Parasympathomimetics


cholinergic agonists
anticholinesterases
cholinergic agonists
 complete cholinergic drugs
◆
acetylcholine ( ACh )
◆
carbachol
 M-cholinoceptor agonist
◆
pilocarpine
 N-cholinoceptor agonist
◆
nicotine
Acetylcholine (ACh)
ACh has both M-R and N-R activity.
M effects:
1. Cardiovascular system
 vasodilation
 decrease heart rate
 negative dromotropic effect
 negative inotropic effect
 shorten atrial refractory period
ACh
2. stimulate intestinal secretions and
motility
3. increase the tone of detrusor urinae
4. increase salivary and bronchiolar
secretion, miosis, contract skeletal
muscle
Carbachol
very similar to ACh
relatively long
duration of action
used to treat
glaucoma
H3C
H3C
N+ CH2CH2OCOCH3
H3C
Acetylcholine (ACh)
H3C
H3C
N+ CH2CH2OCONH2
H3C
Carbacholine
Pilocarpine
(毛果芸香碱, 匹鲁卡品)
-Origin of the Drug
-South American
- Pilocarpus jaborandi
-Isolated in 1875
-Chemical Structure
HC
O
C
CH
O
CH2
CH2
C
HC
N
N
CH3
CH
Pilocarpine
- Parasympathomimetic （Cholinergic agonist)
Pilocarpine
Actions
M-receptor agonist
Eye:
miosis: constrict the pupillae sphincter
muscle, causing miosis (marked
constriction of the pupil).
lower intraocular pressure
accommodate spasm
Eye Fluid Production and Pressure
角
膜
巩膜静脉窦
前
房
小梁网（滤帘）
虹膜
晶状体
睫状体
Types of Glaucoma
Open-Angle Glaucoma
Blocked drainage of aqueous
Anterior chamber open
Blockage at trabecular
meshwork
Closed-Angle Glaucoma
Blocked drainage of aqueous
Anterior Chamber
angle closure
accommodate spasm
Pilocarpine
Gland: increase gland secretion ,
especially sweat gland and salivary
gland .
Smooth muscle: stimulate intestinal and
airway smooth muscle
Cardiovascular: decrease heart rate
Therapeutic use
 glaucoma (open-angle glaucoma and
closed-angle glaucoma)
 iritis: contracts
the pupils to prevent the
adhesion of iris and lens
 xerostomia
Notice: presses inner canthus, prevents absorption
of drugs from nasolacrimal canal, otherwise, it can
enter the brain and cause CNS symptoms, sweating
and salivation.
muscarine (毒蕈碱)
Anticholinesterase agents
ACh在AChE作用下水解过程
Anticholinesterase agents can inhibit
or inactivate AChE, causing the
accumulation of ACh at the cholinergic
receptors. These drugs can thus
provoke M and N receptors resulting in
M and N effects.
Anticholinesterases are classified as
reversible and irreversible inhibitors.
Neostigmine (新斯的明)
It can reversibly inhibit AChE
myasthenia gravis(重症肌无力): an
autoimmune disease caused by antibodies
to the nicotine receptor that bind to the
ACh-R of neuromuscular junctions.
Neostigmine has a direct and indirect
actions on NM-R (end-plate).
Neostigmine
flatulence and uroschesis after operation
antidotes to poisoning from skeletal
muscle relaxant such as tubocurarine
Adverse effects:
include the actions of generalized
cholinergic stimulation, such as
salivation, nausea, vomitting, abdominal
pain and diarrhea.
Physostigmine (毒扁豆碱, eserin)
CH3
O C NH CH3
N
N
CH3
CH3
O
叔胺类可通过BBB
Physostigmine
(H3C)3N
+
CH3
O C N
O
CH3
季胺类不能通过BBB
Neostigmine
Pharmacological action and uses:
Eye: 1) miosis
2) lowers intraocular pressure
3) accommodates spasm
mainly used in glaucoma
What is the difference between physostigmine
and pilocarpine?
Organophosphates
intoxication and rescue
It can irreversibly inhibits AChE
Types:
Agricultural insectcides:
Dipterex （敌百虫）
DDVP （敌敌畏）
Malathion （马拉硫磷）
Parathion （对硫磷，1605）
Systox （内吸磷，1059）
Rogor （乐果）
War gas:
Sarin （沙林）
Soman （梭曼）
Tabun （塔崩）
Mechanism of intoxication
 Organophosphates are “ irre-versible ”
anticholinesterase drugs . Their phosphor
atom combines with AChE by covalent bond
and forms phosphated AChE that is uneasy
to be hydrolyzed.
 The activity of AChE diminishes markedly
and the concentration of ACh increases.
 Administering as soon as possible in
order to prevent enzyme from “aging”.
The way of intoxication:
skin; respiratory tract; gastrointestinal tract
Symptoms of poisoning
1)M-R: Glands, Eye, Bronchial, GI tract
N1-R: both Sympthetic and Para.
2)N-R
N2-R: Skeletal muscle tremor
3)CNS
exciting
inhibition
Emergency treatment
1) Removal any ingested poison (lavage)
Dipterex ---- don’t gastric lavage with
alkaline solution
DDVP
Parathion（1605） ---- don’t gastric lavage
with KMnO4 solution
Mintacol（1600）
2) rescuing with drugs
Atropine anti muscarinc effects
Cholinesterase reactivator
PAM (pralidoxime iodide)
Cholinesterase reactivator
Action and uses:
reactivating the cholinesterase :
effective groups: quaternary nitrogen
combines with phosphated AChE
oxime combines with phosphoryl
phosphated-PAM decomposes
AChE dissociates
It directly combines with freeorganophosphates , prevents them
further combine with AChE
It has marked action on neuromuscular
junctions and promptly inhibits
fasciculation.
Improves CNS symptoms
 It can’t directly antagonize the
accumulated ACh, therefore, it should
be used with atropine
PAM-CL
administered by iv. and im.
Obidoxime (双复磷)
power and longer than PAM and has
atropine like action
easy to penetrate blood-brain barrier
Question: What are the different results between
using atropine and PAM for organophosphate
poisoning? Why?
Chapter 18
Cholinoceptor blocking drugs
M-receptor blocking drugs
N-receptor blocking drugs
M-R blocking drugs
Atropine
Mechanism of action:
competitively antagonist for M-receptor
Atropine
Pharmacological action
 Glands: inhibits glands secretion:
salivary, sweat glands
 Eye:

Mydriasis

increases
intraocular pressure

paralysis of
accommondation
Atropine
 Smooth muscle: relaxes splanchnic
smooth muscle
 Heart: decrease heart rate (blocking M1-R)
higher doses: increase heart rate (blocking M2-R)
antagonize atrioventricular block and arrhythmia
 Blood vessel and pressure: dilation
 central nervous system: excitation
Atropine
Clinical uses
 Antispasmodic: GI tract, ureter and urinary
bladder
 Antisecretory: preanethesthetic medication,
slavers, night sweat
 Ophthalmolic: iritis, retina examination
 Antiarrhythmia: sinus bradycardia,
atrioventricular block
 Shock: infective shock
 Rescue of organophosphates intoxication
Atropine
Untoward effect
Dry mouth, blurred vison, tachycardia, mydriasis
CNS: restlessness, hallucinations
Poisoning rescue
physostigmine
Contraindication
glaucoma, prostatic hypertrophy
depression
Scopolamine (东茛菪碱)
CNS: sedation
Uses: preanesthetic medication
anti-motion sickness
parkinson’s disease
Anisodamine (654-2,山茛菪碱)
Uses:
anti-shock: more powerful effect on peripheral arteriole
gastrointestinal spasm
synthetic mydriatic
Homatropine (后马托品), Tropicmide (托吡卡胺)
mydriasis occurs more rapidly and has a shorter
duration than atropine
synthetic antispasmodic
Propantheline (普鲁本辛)
high selective on gastrointestinal M-R
selective M1-R antagonist
Pirenzepine (哌仑西平), Telenzepine (替仑西平)
gastric ulcer treatment
N-cholinoceptor blocking drugs
 N1-R blocking drugs
(ganglionic blocking drugs)
 N2-R blocking drugs
(skeletal muscular relaxants)
Ganglionic blocking drugs
Mecamylamine (美加明)
Trimethaphan (樟磺咪酚)
Clinical use:
hypertensive crisis
Adverse effects:
many and severe
Skeletal muscular relaxants
 Depolarizing neuromuscular
blockers
succinycholine
 Nondepolarizing neuromuscular
blockers
curare
Depolarizing neuromuscular blockers
Features:
 short time tremor
 tachyphylaxis 快速耐受性
 overdosage can not be reversed by
neostigmine
 no ganglionic blocking action
Succinycholine (琥珀胆碱, scoline)
Clinical use:
rapid endotracheal intubation
Adverse effects:
 apnea
 muscle aches
 hyperkalemia
 hyperthermia
Nondepolarizing neuromuscular
blockers
Features:
I) no muscular fasciculations
2) effect can be increased by other
nondepolarizing agent and other drugs
3) effect can be resisted by neostigmine
4) has autonomic ganglionic blocking effect
5) increase histamine release
Tubocurarine(筒箭毒碱)
Mechanism：
Binding and blocking N2
receptor
relaxation order:
eye, face
neck, trunk,
arms and legs
muscle
death
respiratory
Chapter 19
Adrenoceptor agonists
Drug classification
a, b-receptor agonists
Adrenaline, Dopamine, Ephedrine
a-receptor agonists
Noradrenaline (a1, a2), Phenylephrine (a1),
Clonidine (a2)
b-receptor agonists
Isoprenaline (b1, b2), Dobutamine (b1),
Salbutamol (b2)
a, b receptor agonists
Adrenaline (肾上腺素, epinephrine)
Actions:
 Vessles:
Constricts: skin,mucosa, viscera (a-R)
Dilates: skeletal muscle（b2-R）
Coronary blood flow increases
 Heart:
strengthen contractility, increase heart rate and
conduction velocity （b1-R）
positive klinotropic effect
 Blood pressure:
Adrenaline
small and therapeutic dose:
systolic pressure increase
diastolic pressure unchanged or decrease
large dose: systolic, diastolic pressure increase
Epinephrine reversal
肾上腺素升压作用翻转
All a-adrenergic blockers reverse the a-agonist
actions of Epinephrine.
The vasoconstrictive action
of epinephrine is interrupted,
but vasodilation of other
vascular beds caused by
stimulation of b–receptors is
not blocked.
 Smooth muscle
Adrenaline
bronchial, GI tract and detrusor of bladder
relaxation (b2-R)
 Metabolism
hyperglycemia: increase glycogenolysis in liver
and release of glucagon (b2-R), decrease release
of insulin (a2-R)
lipolysis: free fatty acid increase (b3-R)
 CNS:
large dose: stimulation
Adrenaline
Clinical uses
 cardiac arrest
caused by drown, electric shock
 allergic shock (penicilline)
decrease capillary permeability
get rid of the bronchial muscle spasm
improve the function of heart
emergency treatment of asthma
relaxing bronchospasm, inhibiting allergic substance release and inhibiting mucosa secretion
Adrenaline
 local use
mix with local anesthetics ( decrease absorption
and prolong the duration)
control oozing of capillary blood
adverse effects:
palpitation, anxiety, headache, tremor
arrhythmia and cerebral hemorrhage
Ephedrine (麻黄碱)
Action:
direct stimulate a-and b-R,
promote NA release from
the nerve endings
Feathers:
oral absorption
mild stimulation to CNS
less potent
long duration of action
tachyphylaxis
Dopamine (多巴胺)
Precursor of NA, a-R，b-R and DA-R agonist
Features:
Low dose:
dilate renal, mesentery and coronary artery (D1-R)
Modest dose:
positive inotropic effects, increase BP (b1-R)
High dose:
vasoconstriction, renal blood flow decrease (a1-R)
Dopamine
Clinical uses
Shock: combined with cardiac contractility
decrease and ologuria
Acute renal failure
adverse effects:
very slight，overdose like adrenaline
a-receptor agonist
Noradrenaline (去甲肾上腺素, norepinephrine)
a-R，b1-R agonist
powerful constrictive effect on blood vessel
of skin, mucosa, internal organ
b1-R stimulation in isolated cardiac tissue
both systolic and diastolic pressures increase
Clinical uses:
1.shock and hypotension (drug intoxication)
2.bleeding of esophagus and stomach
Noradrenaline
Adverse effects
1 acute renal failure
2 extravasation: ischemia, necrosis,
(phentolamine and procaine)
Metaraminol (aramine, 间羟胺)
a1-R，a2-R agonist
Treating early shock and hypotension
Selective a1 receptor agonist
Phenylephrine (去氧肾上腺素)
Treatment of supraventricular tachycardia
mydriasis
Methoxamine (甲氧明)
Selective a2 receptor agonist
Clonidine (可乐定)
Used in hypertension
b-receptor agonist
Isoprenaline (异丙肾上腺素)
b1 ，b2-R agonist
Actions:
Heart: cardiac stimulatory action (b1-R)
Vessles: dilate skeletal arterioles (b2-R)
systolic pressure increase or unchanged
and diastolic pressure decrease
Smooth muscle: bronchodilation
Increase in blood sugar and lipolysis
Clinical uses
Isoprenaline
1 heart arrest
2 A-V conductive block
3 shock
4 bronchial asthma
Selective b1-R agonist
Dobutamine (多巴酚丁胺)
Used in myocardial infarction with heart failure
Selective b2-R agonist
Salbutamol (沙丁胺醇)
Mainly used in bronchial asthma
Chapter 20
Adrenoceptor blocking drugs
a-receptor blocking drugs
b-receptor blocking drugs
a-receptor blocking drugs
 a1, a2 -receptor blocking drugs
Short action: Phentolamine (regitine)
Long action: Phenoxybenzamine
 selective a1-receptor blocker
Prazosin
 selective a2-receptor blocker
Yohimbine
Phentolamine 酚妥拉明
(-)NE
a2
Actions: competitive, nonselective a-R blocker
1.vasodilation block a-receptor
direct dilation
2.tachycardia blood pressure , reflex exciting
block presynaptic a2receptor
3.cholinomimetic action
increase mast cell release histamine
Phentolamine
Clinical use
Peripheral vascular disease
Raynaud’s syndrome, acute arterial occlusion
Local use
anti-NE extravasation
Shock
decrease peripheral resistance, increase output of heart
decrease pulmonary artery pressure
Acute myocardial infarction and refractory
congestive heart failure
Diagnosis and treatment of chromaffinoma
Adverse effects
Phentolamine
1. postural hypotensive response
2. induce angina and arrhythmia
3. induce gastric ulcer
Phenoxybenzamine 酚苄明
noncompetitive, nonselective a-R blocker
Selective a receptor blocker
a1-receptor antagonist
Prazosin(哌唑嗪): hypertension and heart failure
a2-receptor antagonist
Yohimbine(育亨宾):used for study
b-receptor blocking drugs
Classification
b1, b2-receptor blockers (nonselective)
1A: no ISA, propranolol (普萘洛尔)
1B: has ISA, pindolol (吲哚洛尔)
b1-receptor blockers (selective)
2A: no ISA, atenolol (阿替洛尔)
2B: has ISA, acebutolol (醋丁洛尔)
a and b receptor blockers
labetalol (拉贝洛尔)
ISA: intrinsic sympathomimetic activity内在拟交感活性
Actions
β-receptor blocking
heart: diminish cardiac output, negative inotropic
and chronotropic effects
blood pressure: reduce blood pressure in
hypertensive patients
bronchial smooth muscle: contraction
metabolism: decrease glucogenolysis and
glucagon secretion
renin: decrease releasing
membrane stable action
intrinsic sympathomimetic activity
Clinical uses
Arrhythmia
Hypertension
Angina pectoris
Chronic cardiac insufficiency
Glaucoma---timolol(噻马洛尔)
hyperthyroidism--- propranolol
Adverse effects
1. Induce bronchospasm
2. Inhibit heart function
3. Peripheral vascular contraction and
spasm
4. Bounce-back phenomena
5. Hypoglycemic reaction, eyeskinmucosa syndrome
中国医科大学药理教研室
聂宏光
基础二楼332室
[email protected]