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American origin, contains Atropine
Chapter 8
Cholinoceptor blocking drugs
Cao Yongxiao 曹永孝
Department of Pharmacology
[email protected];029-82655140
http://pharmacology.xjtu.edu.cn
1
Cholinergic fibers include:
• preganglionic fibers
• parasympathetic fibers
• a few sympathetic
postganglionic fibers
• nervous fibers
controlling adrenal
medulla.
• somatic motor fibers
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Cholinoceptor antagonists are divided into M and N
subgroups based on their specific receptor affinities.
The N receptor antagonists consist of ganglion-blockers
(N1,NN) and neuromuscular junction blockers (N2,NM).
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Basic Pharmacology of the
M Receptor-blocking Drugs
are called parasympatholytic because
they block the effects of parasympathetic
autonomic discharge.
Naturally occurring compounds with anti-M receptor effects have
been used for millennia as medicines, poisons, and cosmetics.
Atropine is their prototype. Many similar plant alkaloids are known.
Hundred of synthetic anti-M receptor compounds have been prepared.
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Pharmacokinetics
Most of antimuscarinic
drugs being tertiary
agents
well absorbed from the
gut and widely
distributed in the body
reaches the CNS
limit the dose tolerated
Scopolamine is rapidly
and fully distributed
into the CNS
where it has greater
effects than most others
The quaternary
derivatives are poorly
taken up by the brain.
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They are
relatively less
effect of CNS
Pharmacokinetics
Atropine disappears rapidly from the blood, t ½ of 2 h.
The effect declines rapidly in all organs except the eye .
Effects on the eye persist for ≥ 3 days.
About 60% of the dose is excreted unchanged in the urine.
The rest appears as hydrolysis and conjugation products.
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Pharmacodynamics
A.
Mechanism of Action:
blocks M receptor reversiblely
The effectiveness varies with tissues.
The most sensitive tissues to
atropine are the salivary, sweat
glands, digestive tract, bladder,
bronchial, and uterus.
The least sensitive is the gastric
parietal cells secreting acid.
Antimuscarinic agents block exogenous
M receptor agonists more effectively
than endogenous ACh.
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B. Organ System Effects
1. Central Nerve System
Atropine has minimal effects on the CNS.
Scopolamine has marked central effects,
producing drowsiness and amnesia.
In toxic doses can cause excitement, agitation,
hallucinations, and coma.
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2. Eye— Block M receptor
Mydriasis
扩瞳
The pupillary constrictor
muscle, iris depends on M
receptor.
Atropine and other antiM drugs block M receptor
and results in dilatation of
iris and mydriasis.
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2. Eye—
Mydriasis
The smooth muscles of the iris
The radial muscle is innervated by
adrenergic fibers to an alpha-1 receptor.
Its contraction by an agonist results in
mydriasis and its blockade results in
miosis
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扩瞳
The sphincter muscle
is innervated by
cholinergic fibers to
M receptors.
Its contraction under
the influence of an
agonist results in
miosis, and its
blockade by atropine
results in mydriasis.
2. Eye— Block M receptor
Mydriasis 扩瞳
intraocular pressure↑升眼压
Atropine
blocks M receptor,
Atropine block M receptor,
inhibits the contraction of
contract the iris, and
thereduce
iris, the angle space of
andanterior
narrow
the angle
chamber
so asspace
to
prevent outflow
of
of anterior
chamber
aqueous humor, increasing
theprevent
intraocular
so the
as to
outflow of
pressure.
aqueous humor, increasing
the intraocular pressure.
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2. Eye—
Mydriasis 扩瞳
intraocular pressure↑升眼压
cycloplegia 调节麻痹
Anti-M drugs block M
receptor, inhibit the
contraction of the ciliary
muscle, result in
cycloplegia.
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Diagram of eye depicting major pathway for outflow of aqueous
humor (heavy arrow) which drains at Schlemm's canal. If the angle
between the iris and the cornea is narrow, a physical impediment
may exist to drainage and the intraocular pressure is increases. This
is exacerbated during mydriasis because the iris contracts toward
that angle (narrow angle glaucoma) to further impede outflow.
The ciliary muscle is a sphincter. When contracting, it relaxes the
suspensory ligaments on the lens.
The lens rounds of its own elasticity to accomodate to near vision.
Under the influence of excess ACh, however, the muscle goes into
ciliospasm, and cannot reaccomodate for far vision.
This occurs in anticholinesterase poisoning.
2. Eye—
Mydriasis 扩瞳
intraocular pressure↑升眼压
cycloplegia 调节麻痹
Anti-M drugs block M
receptor, inhibit the
contraction of the ciliary
muscle, result in
cycloplegia.
Antimuscarinic drugs
reduce lacrimal
secretion.
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3. Cardioavascular system
Sinoatrial node
is controlled by M receptor.
Atropine blocks M receptor and
causes tachycardia.
Lower doses results in initial
bradycardia due to block presynaptic
M receptor which limit ACh release.
Atropine blocks M receptor on
atrioventricular node,
increase the conduction, and the
PR interval of ECG.
In toxic doses, atropine
blocks intraventricular
conduction
Cardiomuscle is controlled by lesser degree of M receptor.
Atropine has no clinical significant effect on西安交大医学院药理学系
it.
曹永孝
Blood Vessels
The skeletal muscle vascular
bed contains M receptor.
Almost all vessels contain
endothelial M receptors that
mediate vasodilation.
The receptors are readily blocked by antimuscarinic
drugs. At toxic doses, and in some individuals at
normal doses, atropine cause cutaneous vasodilation.
But there is little effect on blood pressure.
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4. Respiratory System
Both smooth muscle and secretory
glands of the airway receive vagal
innervation and contain muscarinic
receptors.
Atropine dilates bronchi and inhibits secretion of gland.
The effect is more significant in patients with airway
disease although the antimuscarinic drugs are not as
useful as the β-adrenoceptor stimulants in the treatment
of asthma.
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5. Gastrointestinal Tract
Antimuscurinic drugs have marked
effect on salivary secretion;
Dry mouth occurs frequently.
Atropine inhibits gastric secretion less
effectively, reduces the volume and
amount of acid, pepsin, and basal
secretion in large doses.
Pancreatic and intestinal secretion
are little affected by atropine;
They are primarily under hormone.
Atropine inhibits gastrointestinal movement by blocking M receptor.
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6. Genitourinary Tract—
Atropine and its analogs relax smooth
muscle of the ureters and bladder wall
and slows voiding.
This action is useful in the treatment of
spasm induced by inflammation, surgery,
and certain neurologic conditions,
but it can cause urinary retention in
elderly men with prostatic hyperplasia.
The antimucarinic drugs have no
significant effect on the uterus.
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7. Sweat Glands—
Sympathetic cholinergic fibers innervate
sweat glands.
Atropine suppresses thermoregulatory
sweating.
In adults, body temperature is elevated by
large dose.
In infants and children even ordinary dose
may cause “atropine fever.”
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Therapeutic Applications
A. Central Nervous System Disorders
1.Parkinson’s Disease--It is due to degeneration of dopamine
Parkinson's disease occurs when neurons degenerate
neuron
and
relative
hyperactive
M neuron.
(lose the
ability
to function
normally) in a part
of the
brain called the substantia nigra. Many of these
neurons that degenerate contain the neurotransmitter
called dopamine. As these neurons degenerate,
Centrally
antimuscarinic
preparations
dopamineacting
levels fall,
and the balance between
dopamine and other neurotransmitters, such as
canacetylcholine,
block M receptor
decrease the
is thrown off.and
This neurotransmitter
imbalance
the way muscles
work and
leads toas
activity
of affects
M receptor
to remain
useful
movement problems.
adjunctive therapy in some patients.
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Arvid Carlsson
The Nobel Prize in 2000
Swedenish
The chemical transmitter dopamine is
formed from the precursors tyrosine and
L-dopa and is stored in vesicles. In the
treatment of Parkinson's disease, L-dopa
is given, and is converted to dopamine.
This compensates for the patient's lack of
dopamine.
Dopamine nerve pathways in the brain.
Arvid Carlsson showed that there were
high levels of the chemical transmitter
dopamine in basal ganglia, which
control muscle movements. In
Parkinson's disease nerve cells those
produce dopamine, and whose nerve
fibers project to the basal ganglia die.
This causes symptoms such as tremor,
muscle rigidity and unability to move.
Dopamine, a nerve transmitter
made in the basal ganglia, is
needed for this damping effect.
Other signals pass, by pathway B,
to the basal ganglia; these
damp the signals in pathway A,
reducing muscle tone so that
movement is not jerky.
During movement,
signals pass from the
cortex, via reticular
formation and spinal
Another transmitter,
cord (pathway A), to muscles,
acetylcholine,
inhibits
which
contract.
the damping effect.
Parkinson’s DiseaseDegeneration of parts of the basal
ganglia causes a lack of dopamine.
The basal ganglia are thus prevented
from modifying the nerve pathways
that control muscle contraction.
As a result, the muscles are overly
tense, causing tremor, joint rigidity,
and slow movement.
Most drug treatments
increase the level of
dopamine in the
brain or oppose the
action of ACh.
2. Motion Sickness
Scopolamine is one of the oldest
remedies for seasickness.
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Ophthalmologic Disorders
Accurate measurement of refractive error requires ciliary paralysis.
For adults, the shorter acting drugs are preferred.
For
children,
greater
efficacy
of atropine is
Examining
the the
retina
is facilitated
by mydriasis.
necessary, but the possibility of poisoning is
Antimuscarinic agents,
administered topically
correspondingly
increased.
are extremely helpful in doing the examination.
In the past, anti M drugs have been selected from
the tertiary amine to ensure good penetration.
Now, Glycopyrrolate, a quaternary agent, is as
rapid in onset and as long–lasting as atropine.
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Diagram of eye depicting major pathway for outflow of aqueous
humor (heavy arrow) which drains at Schlemm's canal. If the angle
between the iris and the cornea is narrow, a physical impediment
may exist to drainage and the intraocular pressure is increases. This
is exacerbated during mydriasis because the iris contracts toward
that angle (narrow angle glaucoma) to further impede outflow.
The ciliary muscle is a sphincter. When contracting, it relaxes the
tension of the suspensory ligaments on the lens.
The lens rounds of its own elasticity to accomodate to near vision.
Under the influence of excess ACh, however, the muscle goes into
ciliospasm, and cannot reaccomodate for far vision.
This occurs in anticholinesterase poisoning.
To prevent synechia formation in iritis.
The longer lasting preparation, especially
homatropine, are valuable for this indication.
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C. Respiratory Disorders
Pre-anesthetic administration
Irritant anesthetics such as ether
markedly increased airway secretion
and were associated with frequent
episodes of laryngospasm.
Atropine or scopolamine could prevent these
hazardous effects.
Scopolamine also produces significant amnesia.
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D. Cardiovascular Disorders
Excessive vagal discharge may
result in depression of sinoatrial or
atrioventricular node.
Atropine or similar antimuscarinic
drugs are appropriate therapy in
this situation.
Patients with hyperactive carotid sinus reflexes experience
faintness or syncope as a result of vagal discharge in
response to pressure on the neck, a tight collar.
Antimuscarinic agents may benefit to the disease.
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E. Gastrointestinal Disorders
Anti-M agents can relieve traveler’s
diarrhea and hypermotility. They are often
combined with an opioid antidiarrhead
drug, diphenoxylate.
In this combination, the very low dosage
of the anti-M drugs can decrease
opioid abuse.
Anti M agents are now rarely
used for peptic ulcer disease
in the USA.
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F. Urinary Disorders
Atropine and other antimuscarinic drugs can
relieve the urinary urgency caused by
inflammation bladder disorder.
Oxy-butynin is often used to relieve bladder
spasm after urologic surgery.
Imipramine, a antidepressant drug
with strong antimuscarinic action, has
long been used to reduce incontinence
in institutionalized elderly patients.
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G. Cholinergic Poisoning
Antimusarinic Therapy
Poisoning of cholinesterase inhibitors
can increase the concentration of ACh
in synaptic space and show both the N
and the M effects. Atropine can reverse
the M effects in the CNS as well as the periphery.
Large doses of atropine may be needed to combat
the M effects of extremely potent agent like
parathion (1605) and warfare nerve gases
H. Other Applications
Hyperhidrosis is sometimes reduced by anti-M agents
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Adverse Effects
Treatment with atropine or its congeners directed at one
organ almost always induce undesirable effects in other
organ systems.
Atropine poisoning manifest dry mouth, mydriasis,
cycloplegia, tachycardia, hot and flushed skin, agitation,
delirium, high temperature.
Atropine is dangerous in children.
Poisoning caused by quaternary anti-M drugs is associated
with all of the peripheral signs of parasympathetic blockade.
The poisoning can be treated with cholinesterase inhibitor
such as neostigmine.
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Contraindications
The contraindications are relative.
Obvious muscarinic excess, especially that caused by ChE
inhibitors, can always be treated with atropine.
Glaucoma, especially angle-closure glaucoma, is a
contraindication. Atropine may precipitate angle closure in
patients. In elderly men with prostatic hyperplasia,
antimuscarinic drugs should be avoided.
Nonselective antimuscarinic agents should never be used to
acid-peptic disease. Because they slow gastric emptying and
increase symptoms with gastric ulcer.
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III. Ganglion-Blocking Drugs
These agents block the action of ACh and similar
agonists at the N receptors of autonomic ganglia.
They lack selectivity and have broad side effects so that
they have been abandoned for clinical use.
The ganglionblocking drugs are still important and
useful in pharmacologic
research because of their
ability to block all
autonomic outflow.
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A. Mechanism of Action
Nicotine, carbamoylcholine, succinylcholine and ACh can
depolarize the postsynaptic membrane for long time, leading
to a reduction in receptor sensitivity manifested by flaccid
paralysis. It produces depolarizing ganglion blockade.
Nondepolarizing competitive antagonists
Trimethaphan blocks the N receptor.
Hexamethonium occupy sites on the
ion channel controlled by ACh receptor.
The blockade can be overcome by agonist, ACh.
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Organ system Effects
1. Central Nervous System—
The quaternary amine agents lack central effects
because they do not cross the blood-brain barrier.
Mecamylamine readily enters the CNS.
Sedation, tremor, choreiform movement, and mental
aberrations have all been reported as effects.
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2. Eye
Because the ciliary muscle receive primarily the
parasympathetic nervous innervation, the ganglionblocking drug cause a predictable cycloplegia with
loss of accommodation.
The iris receives both sympathetic and parasympa-
thetic innervation. Because parasympathetic tone is
usually dominant in this tissue, ganglionic blockade
causes moderate dilation of the pupil.
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Cardiovascular System
The blood vessels receive chiefly vasoconstrictor fibers
from the sympathetic nervous system;
Ganglionic blockade cause an obvious decrease of arteriolar
and venomotor tone, and decrease of the blood pressure,
because both peripheral vascular resistance and venous
return are decreased.
Hypotension is especially marked in the upright position,
because postural reflexes are blocked.
Cardiac effects include diminished contractility and,
because the sinoatrial node is usually dominated by the
parasympathetic nervous system, a moderate tachycardia.
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4. Gastrointestinal Tract
Secretion is reduced, although not
enough to treat peptic disease.
Motility is profoundly inhibited, and
constipation may be marked.
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5 Other System
Genitourinary smooth muscle is partially dependent
on autonomic innervation. Ganglionic blockade
therefore causes hesitancy in urination and may
precipitate urinary retention in men with prostatic
hyperplasia.
6. Response to Autonomic Drugs—
Because the effects of cell receptors are not blocked,
patients receiving ganglion-blocking drugs are fully
responsive to autonomic drugs acting on these receptors,
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Clinical Applications ＆Toxicity
Because of the availability of more selective
autonomic blocking agents, the applications of the
ganglion blockers have almost disappeared.
For most patients, the toxicity of the ganglionblocking
drugs are intolerable except for acute use.
Mecamylamine may reduce nicotine craving.
Trimethaphan is occasionally used in hypertensive
emergencies.
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Deadly nightshade (Atropena
belladonna) is the natural source of the
alkaloid atropine. The term atropena is
derived from Atropos because of its high
toxicity. Atropos is the Greek goddess of
Fate and is responsible for the final part of
a mortal life, the unturning inevitability of
death. Atropine was a popular choice of
poison amongst professional poisoners
during the Middle Ages because of the
slowness of their effects which allowed the
perpetrator to escape before suspicions
were aroused. According to the Scottish
legend, the soldiers of Macbeth slipped
atropine into the drinks of the invading
Danes then slaughter them in their slumber.
In Roman time, ladies in the Court used the
juice from the berry to dilate their pupils to
make them look more sensual and
attractive and hence the name belladonna
(beautiful lady). Atropena belladonna
can be translated as femme fatale. In
ophthalmology, it is used in cycloplegic
refraction, post-operative dilatation as
following trabeculectomy and in the
treatment of anterior uveitis to prevent
posterior synechiae. Atropine also dumbs
nerve endings and lessen pain
when applied locally.
atropine