science lesson

1. 1
Cao Yongxiao 曹永孝
Department of Pharmacology 医学院药理学系
yxy@xjtu.edu.cn;029-82655140 科教楼 805
http://pharmacology.xjtu.edu.cn
Chapter 7
Cholinoceptor-activating Drugs
Amanita muscaria
from which muscarine
is isolated

2. ．
西安交大医学院药理学系 曹永孝
yxy@xjtu.edu.cn; 029-82655140
Cholinoceptor-activating
drugs (cholinomimetics)
are the ones that mimic
the effects of ACh.
They are classified by
their mechanism of
action.
The drugs are similar to
ACh actions
Mode of action of cholinoceptor-activating drugs

3. ACh can agonize the whole efferent nerve system, produce very broad effects
西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

4. Effects of cholinomimetics are similar to the effects of
cholinergic fibers; include:
• somatic motor fibers,
• preganglionic autonomic fibers,
• parasympathetic fibers,
• a few sympathetic
postganglionic
fibers (controlling
sweat gland and
blood vessel in
skeletal muscle)
• nervous fibers
controlling adrenal
medulla.

5. Cholinergic Transmission
After released,
ACh binds to
and activates
pre- and
postsynaptic
ACh receptors,
showing the
action of
transmitter.
Then, ACh is
hydrolyzed rapidly
by acetylcholin-
esterase (AChE),
terminating the
action of the
transmitter.
When an AP reaches
the terminal, influx of
Ca2+ is triggered,
which facilitates the
fusion of the vesicular
membrane with the
terminal membrane
and results in the
release of ACh into
synaptic space.
One AChE can
hydrolyze 6 x 105
ACh per minute.
西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

6. Some cholinomimetic
drugs bind directly to
and activate
cholinoceptors
(cholinoceptor agonist)
Others act indirectly
by inhibiting the
hydrolysis of
endogenous ACh
(anticholinesterases).
Cholinoceptor agonists can be
divided into two groups based on
the mode of action: cholinoceptor
agonist and anticholinesterases
西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140
Cholinergic
Transmission

7. Basic Pharmacology of
Cholinoceptor Agonists
are divided into two groups based on the chemical structure:
Choline esters: acetylcholine, methacholine, carbamic acid, carbacochol
Alkaloids: pilocarpine, muscarine, oxotremorine,
nicotine, lobeline, dimethylphenypiperazinium.
Many these drugs have effects on both M and N receptors
A few of the drugs are highly selective for M or N receptors.
Non-selective drugs have more side effects than selective one.
西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

8. Cholinoceptor agonists
can be hydrolyzed in the
Gastrointestinal tract.
Their absorpation decreases.
So does their bioavailability

9. Cholinoceptor agonists can
be hydrolyzed especially by
cholinesterase (ChE) in
effective location.
Acetylcholiesterase (AChE): true, indeed ChE;
Pseudocholinesterase
ACh is hydrolyzed by ChE rapidly. One AChE can hydrolyze 6x105 ACh per minute.
When intravenous bolus injection, ACh has a brief effect, 5-20 s.
When intramuscular and subcutaneous injection, ACh produces local effect.
Methacholine, carbacol and bathanechol are resistance to
hydralysis by ChE, have longer duration of action.
β-methyl group reduces potency of the drug at N receptor.

10. Pharmacokinetics
Choline esters, being hydrophilic, are poorly
distributed in the CNS.
Blood-Brain Barrier (BBB) is
the specialized system through
both physical (tight junctions)
and metabolic (enzymes)
barriers to protect the brain
from harmful substances in the
blood stream, while supplying
the brain with the required
nutrients.
西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

11. Pharmacokinetics
Choline esters, being hydrophilic, are poorly
distributed in the CNS.
Unlike peripheral capillaries that allow relatively free
exchange of substance across / between cells, the BBB strictly
limits transport into the brain. Thus the BBB is often the rate-
limiting factor in determining permeation of therapeutic drugs
into the brain.
西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

12. Pharmacoldynamics
.
ACh activates M and N
receptors on post-
synaptic membrane of
effectors to alter organ
function directly.
ACh activates M
receptors on presynaptic
membrane to inhibit the
release of ACh

13. Clinical Pharmacology
The major therapeutic
uses of the cholinoceptor-
activating drugs are for
diseases of the eye, the
gastrointestinal and
urinary tracts, the
neuromuscular junction
and the heart.

14. Clinical Uses
Glaucoma is
characterized by
increased intraocular
pressure, which can
result in vision loss.
Muscularinic stimulants
(pilocarpine) reduce
intraocular pressure.
A. The Eye elders

15. The intraocular
pressure is formed
by aqueous humor
which is produced
by the blood vessels
in the ciliary body.
Clinical Uses: Glaucoma
西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140
It flows into posterior chamber, through the pupil into the
anterior chamber, and then drains into the episcleral vein
via the trabecular meshwork and the canal of Schlemn

16. M receptor agonists contract the iris and
increase the angle space of anterior chamber so
as to facilitate outflow of aqueous humor,
decreasing the intraocular pressure.
西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

17. Acute angle-closure glaucoma is a medical
emergency that is treated with both a M
receptor agonist and a AChE inhibitor.
Open-angle glaucoma is not amenable to the
drugs.
For chronic glaucoma,
these drugs have been
largely replaced by
topical β-blockers and
prostaglandin
derivatives
西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

18. B. Gastrointestinal tract
Pilocarpine
The disorders are
characterized by
depression of
smooth muscle
activity, which
result in
disfunction of
gastrointestinal
movement.
Muscularinic stimulants increase the tone and
induce movement of gastrointestine.
西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140
Ileus, intestinal inflation;
congenital megacolon

19. B. Gastrointestinal tract
Pilocarpine, reflux esophagitis,
valve
It is sometime
used to increase
the tone of the
lower esophageal
sphincter in reflux
esophagitis.
西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

20. 3 Urinary tracts
M receptor agonist
can excite M
receptor on bladder
to treat urinary
retention which may
occur post-
operatively or
postpartum or
secondary to spinal
cord injury.
西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

21. The dry mouth
is due to decrease of salivary secretion
Pilocarpine and
cevimeline
increase salivary
secretion by
exciting M
receptor to treat
dry mouth.
西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

22. Cholinoceptor-activating
drugs have broad effects.
The selectivity is poor.
Treatment with them directed
at one organ almost always
induces undesirable effects in
other organs.
The toxic potential varies
depending on their absorption,
access to the central nervous
system and metabolism.
Adverse reaction and toxicity
西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

23. A. Muscarinic stimulants
Nausea, vomiting, diarrhea, abdominal pain, salivation,
sweating, cutaneous vasodilation, and bronchial
constriction.
They are all due to excitement of M receptors. The
effects can be blocked by atropine.
Certain mushrooms contain muscarinic alkaloids
which can cause typical signs of muscarine.
西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

24. B. Nicotinic stimulants
2. Chronic toxicity
One Study by David McAlary, Washington, 17 Nov. 2005
Lifestyle and Environmental Factors Cause One-Third of
Global Health Problem
Leading the list of causes is smoking.
Cigarette smocking is the largest single preventable cause of illness
and premature death
Nicotine itself is the only common cause
of this type of poisoning.
The chronic toxicity is more important than acute one
.
1. Acute toxicity
The fatal dose of nicotine is approximately 40 mg, which is the
amount in two cigarettes. Burning can destroy nicotine.
西安交大医学院药理学系 曹永孝 yxy@xjtu.edu.cn; 029-82655140

25. I am glad to share my knowledge with you,
and I want you to become a master
of the subject, pharmacology
Thanks a million
for your attention