Transcript 2 receptor

Pharmacology of the nervous
system
Shi-Hong Zhang (张世红), PhD
Dept. of Pharmacology,
School of Medicine, Zhejiang University
[email protected]
Peripheral
Nervous
System (PNS)
Efferent
Division
Autonomic
System (ANS)
Afferent
Division
Somatic
System
Parasympathetic
Sympathetic
Enteric
The Enteric Nervous System (+SNS/PSNS)
Sympathetic stimulation causes:
•
•
•
•
•
•
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 （蠕动） 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 of the GI tract
Nervous System
Drugs that produce their
Peripheral
Nervous
System (PNS)
Efferent
Division
Autonomic
System (ANS)
Central
Nervous
System (CNS)
Afferent
Division
Somatic
System
Parasympathetic
Sympathetic
Enteric
Organization of the nervous system
primary therapeutic
effect by mimicking or
altering the functions of
autonomic nervous
system are called
autonomic drugs.
Neurotransmitters
• Synthesis
• Storage
• Release
• Degradation
Receptors
• Activation
• Blockade
Drug actions and classification
(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
Pharmacology of
efferent nervous system
• 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
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)
ACh inactivation
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
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, tear, salivary;
insensitive: GI tract);
• Eye (contraction of sphincter muscle of iris: miosis;
contraction of ciliary muscle睫状肌: 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 ）
- 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)
A
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 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新斯的明
Irreversible: organophosphates 有机磷酸酯类
Cholinesterase reactivators: pralidoxime iodide
碘解磷定
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 (Botox, 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)
Nicotinic receptor agonists (N受体激动剂)
ACh Derivatives
Bond
cleaved
by AChE
乙酰胆碱
醋甲胆碱
卡巴胆碱
氯贝胆碱
AChE resistant
ACh Derivatives
Bethanechol 氯贝胆碱is most commonly used, particularly
post-op for the treatment of paralytic ileus and urinary
retention
Natural Muscarinic Agonists
槟榔碱
毛果芸香碱
毒蕈碱
Nicotinic potency
• Arecoline: areca or betal nuts (India,E. Indies)
• Pilocarpine: pilocarpus (S. Amer. shrub)
• Muscarine: amanita muscaria (mushroom)
“Food” Poisoning
•
Poisoning causes muscarinic
overstimulation：
- salivation, lacrimation, visual
disturbances;
Amanita muscaria
- abdominal colic and diarrhea
伞形毒蕈
- bronchospasm and bradycardia
- hypotension; shock
•
Atropa belladonna
颠茄
Treatment is with atropine
Pilocarpine
(1) Eyes
• Miosis (缩瞳): contraction of sphincter muscle of iris
• Lowing intraocular pressure: enlarging angle of anterior
chamber, increasing drainage of aqueous humor
• Spasm of accommodation (调节痉挛): contraction of
ciliary muscle, contraction for near vision
• Ophthalmological 眼科 uses
Glaucoma 青光眼: narrow (closed)- or wide (open)-angles
used for the emergency, lowering intraocular pressure
Iritis: miotics缩瞳药/mydriatics扩瞳药
Ciliary muscle
(dilation)
Canal of Schlemm
mydriasis
zonule
Posterior
chamber
Anterior
chamber
lens
iris
paralysis of
accommodation
far sight
atropine
spasm of
accommodation
miosis
zonule
Anterior
chamber
Ciliary muscle
(contraction)
near sight
pilocarpine
Circulation of aqueous humor
Glaucoma
• Open-angle glaucoma：
disease of the aging eye increased intraocular
pressure, degeneration of
the optic head, and
restricted visual field
• 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: 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解毒剂 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 新斯的明
Irreversible: organophosphates 有机磷酸酯类
Cholinesterase reactivators: pralidoxime iodide
碘解磷定
Acetylcholinesterase (AChE) Activity
AChE Inhibitors
A. Competitive (reversible)
B. Carbamates (氨甲酰类slowly reversible)
C. Organophosphates (irreversible)
依酚氯铵
These agents are
reversible and are
used medically
(glaucoma or MG)
新斯的明
neostigmine
毒扁豆碱
These agents are
irreversible and
are used as
pesticides or for
glaucoma
Acetylcholinesterase Inhibitors:
Reversible
Edrophonium (依酚氯铵)
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.
Other reversible ACHEI: tacrine 他克林, donepezil 多奈哌齐
Acetylcholinesterase Inhibitors: Carbamates
Inhibitory Effects are slowly
reversible
Representative Drugs
neostigmine (quaternary amine 季铵)
pyridostigmine (quaternary amine)
physiostigmine (tertiary amine 叔胺)
quaternary amines effective in periphery only
tertiary amines effective in periphery and CNS
（fat-soluble）
Neostigmine 新斯的明
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
1.
Myasthenia gravis: symptomatic treatment
overdose: cholinergic crisis
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
2.
Paralytic ileus 麻痹性肠梗阻urinary retention: post operative
abdominal distension and urinary retention
3.
Paroxysmal supraventricular tachycardia（rarely use）
4.
Antidote for tubocurarine ( 筒 箭 毒 碱 ) and related drug
poisoning
5.
Glaucoma
Neostigmine
Adverse effects
• Cholinergic effects: muscarinic and nicotinic effects,
treated with atropine (muscarinic)
• Contraindications：
mechanical ileus（机械性肠梗阻）
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
For ophthalmic use
梭曼
Dichlorvos 敌敌畏
对硫磷
对氧磷
Dimethoate 乐果
马拉硫磷
马拉氧磷
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)
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.
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,
large 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，碘解磷定)
– Pralidoxime chloride （氯解磷定）: safer than PAM
– Obidoxime chloride（双复磷）: two active oxime
groups
Organophosphates
Pralidoxime （解磷
定）can restore
AChE activity if
administered soon
after toxin exposure.
• Conjugating with
organophosphate by
oxime group;
• Conjugating with free
organophasphates
Why isn’t this ACHEI pesticide neurotoxic to humans?
Malathion马拉硫磷
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, galanthamine)
 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 (botox, blocks ACh release)
Muscarinic Antagonists
(Antimuscarinic drugs)
Tertiary amines（叔铵）
Quaternary amines（季铵）
东莨菪碱
异丙托铵
噻托溴铵
Atropa belladonna
颠茄
Datura sp.
洋金花
Datura stramonium
曼陀罗
Henbane Seed
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调节麻痹
Ciliary muscle
(dilation)
Canal of Schlemm
mydriasis
zonule
Posterior
chamber
Anterior
chamber
lens
iris
paralysis of
accommodation
far sight
atropine
miosis
spasm of
accommodation
zonule
Anterior
chamber
Ciliary muscle
(contraction)
near sight
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
1. 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麻醉前用药
(4) Bradycardia
sinus or nodal bradycardia, A-V block
(5) Antidote for organophosphate poisoning
(6) Septic shock 感染性休克
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 in speaking, swallowing & urinating; and
hot, red, dry skin
•
High: above plus ataxia, hallucinations幻觉 & delirium
谵妄; coma
Atropine
3. Adverse effects
(3) Detoxication
Supportive treatment
Symptomatic treatment: e.g. diazepam for CNS symptoms.
Antidote: Physostigmine or pilocarpine
(4) Contraindications
glaucoma, prostatauxe 前列腺肥大, fever
Scopolamine东莨菪碱
• 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 (relieve
spasm of vascular smooth muscles)
Synthesized surrogates
• Tropicamide 托吡卡胺: mydriatic, cycloplegic
shorter duration (1/4 day)
• Propantheline 丙胺太林，普鲁本辛
poor absorption (po) and BBB penetration
•
•
•
•
antispasmodic effects in GI, treatment of peptic ulcer
Ipratropium 异丙托铵: asthma
Benztropine 苯托品: Parkinson’s disease
Trihexyphenidyl 苯海索
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:
Depolarizing: succinylcholine 琥珀酰胆碱
Non-depolarizing: drugs act as competitive antagonists
d-tubocurarine 筒箭毒碱
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司可林)
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 (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 be
used 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)
NM receptor antagonists
(Neuromuscular blocking drugs)
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)
Tubocurarine
• Effects: competitive blockade of NM receptors
• Uses: adjuvant medication for 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)
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
- results in irreversible flaccid paralysis (松弛性瘫痪) in
muscles
Acts by cleaving
SNAP proteins →
inhibits ACh release
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 斜视), blepharospasm
(eyelid spasm), dystonia (abnormal tonicity).
• Excessive sweating
• Cosmetic procedures ( “frown lines” or “crow’s feet”鱼尾纹)
Note: effects can last for ~3-6 months.
Pharmacology of
efferent nervous system
• Cholinergic Pharmacology
• Adrenergic Pharmacology
Noradrenergic Nerve:
Synthesis, storage
and release of NE
Tyrosine
tyrosine hydroxylase (TH)
L-DOPA
DOPA decarboxylase
dopamine (DA)
dopamine beta-hydroxylase (DBH)
norepinephrine (NE)
• Uptake
neurotransmitter transporters
– uptake 1: neuronal uptake
– uptake 2: non-neuronal uptake
• Enzymatic degradation
– monoamine oxidase (MAO)
– catechol-O-methyltransferease
(COMT)
Regulation of NE Synthesis and Turnover
Tyrosine hydroxylase (TH) activity is rate limiting
TH activity is inhibited by NE product
TH activity is modulated by presynaptic autoreceptors
- alpha2 receptors can reduce NE release
- beta2 receptors can increase NE release
Presynaptic heteroreceptors can modulate NE
release
- ACh can reduce NE release
Tyrosine hydroxylase activity increases or decreases
to maintain steady-state levels of norepinephrine.
The above processes contribute to regulation of
steady-state NE levels (rate of synthesis = rate of
output)
Catecholamine
Biosynthetic Pathway
Norepinephrine and Epinephrine
Synthesis in the Adrenal Medulla
- PNMT is located in the cytosol
- DBH is located in vesicles
- EPI is stored in vesicles.
- EPI (~80%) and NE (~20%) released into
blood
NE
NE
PNMT
EPI
Chromaffin cell
EPI
NE Metabolism
- takes place within the same cells where the amines are synthesized, and in liver
- Extraneuronal O-methylation of norepinephrine and epinephrine to metanephrines
represent minor pathways of metabolism.
MHPG(3-甲氧4-羟苯乙二醇):
was used as
an index of CNS NE turnover
but generated mostly from
periphery
VMA(香草扁桃酸):
sometimes used as
an index of NE turnover
Sulfate conjugates
also prevalent
or MHPG
Adrenergic Receptor Subtypes & G-Protein
Coupled Mechanisms
a1 Adrenergic Receptors:
Phospholipase C activation, IP3 increase through Gq
 mechanism: mobilizes and increases intracellular free
calcium
 effects: primarily smooth muscle contraction
a2 Adrenergic Receptors:
Inhibition of adenyl cyclase through Gi proteins
 mechanism: decreases intracellular cAMP levels
 effects: decreased protein phosphorylation, decreased
cellular function
Adrenergic Receptor Subtypes & G-Protein
Coupled Mechanisms
β Adrenergic Receptors:
Activation of adenyl cyclase through Gs proteins
 mechanism: increases intracellular cAMP levels
 effects: phosphorylation of intracellular proteins 
smooth muscle relaxation, cardiac muscle contraction
可乐定
去氧肾上腺素
异丙肾上腺素
q
Four Major Activators of the
Adrenergic System
1 Hypoglycemia
2 Hypothermia
3 Hypoxia
4 Hypotension
•
•
Hypoxia - response is mainly cardiovascular: b1 receptors via
SNS NE increase heart rate & contractility, resulting in
greater cardiac output; b2 receptors via adrenal Epi
vasodilate blood vessels in muscle, increasing oxygen
delivery, and mediate bronchodilation to facilitate oxygen
intake.
Hypoglycemia - response is mainly metabolic, but b2
vasodilation in muscle increases glucose (as well as oxygen)
delivery.
Response to
Hypoglycemia
The release of E
(and to a lesser
extent NE) by the
adrenal is in direct
response to falling
blood glucose
levels
Insulin injection
(insulin injection)
Glycogenolysis
•
•
•
•
The brain and muscle must have glucose
The main sites of glycogenolysis are the
liver and muscle
Glycogen is broken down by glycogen
phosphorylase
This enzyme is activated by both PKA and
PKC through stimulation of b2 and a1
adrenergic receptors, respectively
Gluconeogenesis
•
The liver and kidney are the key sites
•
Substrates: lactate (from muscle) and glycerol
(from fat)
•
Several enzymes in the pathway are activated by
PKC through a1 stimulation
•
Both glycogenolysis & gluconeogenesis are
indirectly stimulated by facilitating release of
glucagon (b2) & inhibiting release of insulin (a2)
Lypolysis
•
Lipases are stimulated by b (esp. b3) receptors
Energy Mobilization by Epinephrine
Response to Hypothermia:
1 - Piloerection
2 - Peripheral vasoconstriction
3 - Thermogenesis
-Brown fat
a) activation
b) proliferation
Summary: Adrenoceptors
a receptors
• a1 receptors: vasoconstriction: increased
peripheral resistance, BP↑; contraction of radial
muscle of iris: mydriasis
• a2 receptors: CNS, presynaptic membranes of
adrenergic nerves: vasodilatation, inhibition of NE
release; inhibition of insulin release
Summary: Adrenoceptors
b receptors
• b1 receptors: heart stimulation: contractility↑,
automaticity↑, conduction↑, oxygen-consumption↑, cardiac
output↑; increased lipolysis
• b2 receptors: bronchodilation; slight vasodilation;
increased muscle and liver glycogenolysis; increased
release of glucagon
• b3 receptors: lipolysis, thermogenesis
Drug classification
1. Direct actions on the receptors
Agonists
Antagonists
2 Indirect actions via affecting transmitters
Synthesis (L-dopa)
Transport and storage (imipramine丙咪嗪, reserpine 利舍平)
Release (ephedrine 麻黄碱, amphetamine 安非他明)
Inactivation (MAOI)
Drug classification
3. 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
Structure-activity relationship of
catecholamines and related compounds
•Strong efficacy
•Short duration
•No entry to CNS
• Receptor activation
苯乙胺
•Resistant to MAO
麻黄碱
Methamphetamine
甲基苯丙胺
• Catecholamine
• Non-catecholamine
苯乙胺
– Indirect-acting by
– High potency in
causing the release of
activating a or b
stored catecholamine.
receptors
– Not inactivated by
COMT; some are poor
– Rapid inactivation by
substrate for MAO
COMT and by MAO
(orally active, a
– Poor penetration into the
prolonged duration of
CNS
action)
– Greater access to the
CNS
Adrenergic agonists
Norepinephrine, Noradrenaline
Pharmacological effect
a1, a2 receptor agonists
(1) Vascular effects：
a1：vasoconstriction (skin, renal, brain,
hepatic, mesenteric, etc.), blood flow 
a2：inhibiting NE release
(2) Blood pressure：
Systolic BP , Diastolic BP (especially at larger doses)
Norepinephrine
(3) Cardiac effects：
weak direct stimulation (b1);
inhibition via reflex (in vivo)
Net result: little cardiac stimulates
Effects of Norepinephrine on BP and HR
Norepinephrine
Clinical uses (limited therapeutic value)
(1) Shock
• used in early phase of neurogenic shock: small doses
and shorter duration
(dopamine is better; replaced by Metaraminol 间羟胺，α
agonist and NE releaser, weaker but longer effect)
(2) Hypotension due to drug poisoning
• especially for chlorpromazine （氯丙嗪）
(3) Hemorrhage in upper alimentary tract (上消化道)
• orally given after dilution
Norepinephrine
Adverse effects
(1) Ischemia and necrosis at the site of iv
administration
- relieved by filtrating the area with phentolamine (酚妥拉明，
a receptor antagonist)
(2) Acute renal failure
- avoiding larger doses and longer duration; monitoring
urinary volume
(3) Contraindication
- hypertension, arteriosclerosis, heart diseases, severe
urinary volume , microcirculation disorders
a1 receptor agonists
Phenylephrine (去氧肾上腺素)
Methoxamine (甲氧明)
• Induces reflex bradycardia, used in hypotension
under anesthesia and drug poisoning,
paroxysmal supraventricular tachycardia ；
• Phenylephrine: Mydriasis: pupillary dilator
muscles, no or less effect on intraocular
pressure, short-acting (for several hours);
act as a nasal decongestant (鼻血管收缩药)
a2 receptor agonists
• Clonidine可乐定:
Uses: antihypertensive drug; can be administered as
transdermal patch (permits continuous administration)
Mechanism of action:
a2 - adrenergic partial agonist; actions
predominantly in CNS
lowers blood pressure by inhibiting sympathetic
vasomotor tone
a2 receptor agonists
• Clonidine
Adverse effects: iv administration may result in
transient increase in blood pressure (activation of
post-synaptic receptors); dry mouth, sedation
a2 receptor agonists
Oxymetazoline (羟甲唑啉): a nasal decongestant
Apraclonidine (阿可乐定): decreases intraocular
pressure.
Epinephrine, Adrenaline
Pharmacological effects ： a 1, a2, b1, b2
receptor agonists
(1) Cardiac effects
b1: contractility  (positive inotropic),
HR  (positive chronotropic),
cardiac output ,
oxygen consumption ,
induces arrhythmia
Epinephrine, Adrenaline
Pharmacological effects ： a 1, a2, b1, b2
receptor agonists
(2) Vascular effects
a1：vasoconstriction (skin, mucous, viscera),
especially at larger doses
b2：vasodilatation of skeletal muscles
and coronary vessels
Concentration-dependent response in
vascular smooth muscle to epinephrine
Predominant Effects
low [EPI] β2 > α
high [EPI] α > β2
Epinephrine
(3) Blood pressure- two phases
Systolic BP, Diastolic BP↓(slight) , pulse pressure 
Epinephrine
(4) Respiratory
b2：dilatation of bronchial smooth muscles
(Bronchodilatation)
inhibition of degranulation of mast cells
a1：reducing congestion and edema of bronchial mucosa
(5) Gastric and bladder smooth muscles: relaxation (b2)
(6) Eye: intraocular pressure ↓ (α1,2)
(7) Metabolic effects
blood glucose  (b2 and a1,2, hyperglycemia);
free fatty acids  (b, lipolysis)
Epinephrine
Clinical uses
Topical uses:
Systematic uses:
• Adjuvant of
local anesthesia
• Cardiac arrest
• Bleeding
• Glaucoma
• Anaphylactic
shock (过敏性休克)
• Acute bronchial
asthma
Epinephrine
Adverse effects
(1) Cardiac arrhythmias
(2) Hemorrhage (cerebral or subarachnoid) :
reason: a marked elevation of BP
(3) Central excitation: anxiety, headache...
(4) Contraindications: heart diseases, hypertension,
coronary arterial disease, arteriosclerosis （动脉硬化）,
hyperthyroidism （甲亢）
Ephedrine 麻黄碱
HO
NH
CH
CH
OH
CH3 CH3
HO
Ephedrine
CH
CH
OH
Epinephrine
NH
CH3
CH2
CH
NH
CH3 CH3
Methamphetamine
Properties：
- Promoting release of NE, weak agonist effects on a1、a2、
b1、b2 receptors
- chemically stable, orally effective；
- less potent but longer action duration;
- central stimulating: alertness , fatigue ↓, prevents
sleep (adverse effects)
- Tachyphylaxis (快速耐受).
Ephedrine
Clinical uses
(1) Prevention of hypotension: anesthesia
(2) Nasal decongestion: nasal drop
(3) Bronchial asthma: mild, chronic cases
(4) Relieving allergic disorders: urticaria 风疹,
angioneurotic edema 血管神经性水肿
Dopamine
Pharmacological effects:
a, b receptor, dopaminergic
receptor agonists
(1) Cardiac effects：b1 receptor,
weak
(2) Vascular effects：
DA receptor: vasodilatation of
renal, mesenteric arteries (small
doses);
a1 receptor: vasoconstriction of
skin, mesenteric/renal vessels
(larger doses)
Dopamine
Clinical uses
(1) Shock
cardiac and septic (感染性) shock
(2) Acute renal failure
combined with furosemide
Adverse effects
short-lived; tachycardia, arrhythmia, reduction
in urine flow (renal vasoconstriction)
Isoproterenol, Isoprenaline:
Pharmacological effects:
b1 , b2 receptor agonists, NE releaser
(1) Cardiac effects (b1 receptor)
(2) Vascular effects and blood pressure
b2 receptor: dilatation of skeletal
muscles and coronary vessels；
SP , DP  or , pulse pressure 
(3) Bronchodilatation (b2 receptor)
(4) Metabolism
Promoting effects as epinephrine
Effects of catecholamines（therapeutic doses）
Predominant Effects:
NE : a & b1 effects
EPI : b1, b 2 then at higher concentrations a effects predominate
ISO: b1 and b 2
Isoproterenol
Clinical uses
(1) Cardiac arrest / A-V block: in emergencies
(2) Shock: replaced by other sympathomimetics
(muscular vasodilatation)
(3) Bronchial asthma
Adverse effects
(1) Heart stimulation, arrhythmia
(2) Contraindications: coronary heart disease,
myocarditis （心肌炎）, hyperthyroidism
b1 receptor agonists
Dobutamine （多巴酚丁胺）
• Heart failure (after cardiac surgery or
congestive HF or acute myocardial
infarction; short-term treatment)
• Cardiac stimulation
b2 receptor agonists
Terbutaline (特布他林)
• Uses: Bronchial asthma
dilation of bronchial smooth muscle; b2 > b1 agonist
(partially selective): preferential activation of pulmonary
b2 receptors by inhalation.
Use: Premature Labor (ritodrine).
• Adverse effects:
headache, cardiac stimulation and skeletal muscle fine
tremor (b2 receptors on presynaptic motor terminals; their
activation enhances ACh release).
INDIRECT-acting drugs (summary)
参考书目
• 杨世杰主编《药理学》人民卫生出版社2010
第二版
• Katzung BG, Basic & Clinical
Pharmacology (10th edition), 2007.
• Lipincott’s illustrated reviews—
Pharmocology (2nd edition), 2002