Drugs and

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Drugs and The Nervous System
Part Deux - The Cholinergic System
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Possible Mechanisms for a Drug or Toxin

• stimulate a receptor (agonist)
• block a receptor (antagonist)
• prevent the synthesis of a neurotransmitter (NT)
• stop the storage of a NT in the synaptic vesicles
• prevent exocytosis
• enhance exocytosis
• cause hyperpolarization of a synaptic membrane
• inhibit the breakdown of a NT
• prevent the reuptake of a NT or its precursor
• enhance the binding of a NT

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Scheme
Cholinergic System
muscarinic(M)
agonists
nicotinic(N)
muscarinic(M)
antagonists
nicotinic (N)
factors affecting the release of acetylcholine
factors affecting the breakdown of acetylcholine
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CHOLINERGIC AGONISTS
muscarinic agonists
found in very small amounts
doesnt cross the B3
M1 excitatory M2 inhibitory
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Other toxins in Amanita mushrooms
slow mushroom poisoning
different mechanisms of action
amanita phalloides (death cap)
no symptoms for 6-15 hours
Then - violent gastroenteritis fever,
tachycardia, hyperglycemia, dehydration,
electrolyte imbalance, liver dysfunction and
necrosis, renal failure.
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Still more toxins
can cross B3
25mg/kg mushroom
causes ethanol- like intoxication
acts like glutamic acid - excitatory
can cross B3
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Back to muscarinic agonists
open angle glaucoma is the most common form -
lack of fluid drainage
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muscarinic agonists
It is estimated that 10-25 of the worlds
population chews betel quid.
photos taken by T. Bailey Inle, Myanmar (12/01)
mixtures with tobacco and other materials can be
carcinogenic.
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muscarinic agonists
not broken down by acetylcholinesterase
persistent in nervous system
nicotinic agonists
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CHOLINERGIC ANTAGONISTS
antimuscarinics
members of the Solanaceae family
potatoes, tomatoes, eggplant, peppers, Datura,
Jimson weed, thornapple, mandrake...
belladonna alkaloids
atropa belladonna
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antimuscarinics
Datura
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antimuscarinics
The Three Fates Moirae
Clotho Lachesis Atropos
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antimuscarinics
henbane
fetid nightshade devils eye...
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antimuscarinics
monkshood
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antimuscarinics
incapacitating chemical warfare agent
dispersed as an aerosolized solid
odorless and nonirritating clinical effects are
not evident for 30 minutes to 24 hours
wide body distribution crosses B3
symptoms stupor confusion panoramic
illusions hallucinations
BZ, Agent 15 (Iraq)
cholinergic antagonist at muscarinic receptors in
smooth muscle, exocrine glands, autonomic
ganglia, and the brain
ICt50 - concentration need to produce
incapacitation in 50 of an exposed group - 112
mg-min/m3. LCt50 - 200,000 mg-min/m3
CWC - Schedule 2
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antinicotinics
neuromuscular blockaders
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antinicotinics
depolarizing blockade
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antinicotinics
cobrotoxin
high affinity nicotinic antagonist
71 amino acids 5 S-S bridges nondepolarizing
blockade
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a-bungarotoxin
antinicotinics
Southeast Asian krait
2 chains 74 amino acids _at_ 5 S-S
bridges nondepolarizing blockade
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antinicotinics
antihypertensive used to stop smoking or chewing
tobacco
June 25, 2001 The study volunteer who died during
research at the Johns Hopkins Asthma and Allergy
Center was an otherwise healthy woman. Ellen
Roche was employed at the Center and volunteered
to participate in a study in which she was
required to inhale a blood pressure medication
known as hexamethonium. Roche died one month
after inhaling the drug. Researchers are baffled
as to why the woman died. The investigation
centers on hexamethonium's tendency to constrict
the airways in the human body. Johns Hopkins and
the National Institutes of Health have warned
other research facilities throughout the United
States to pay close attention to study
participants who inhale hexamethonium. On
Thursday, the U.S. Department of Health and Human
Services announced that it was launching an
investigation into the incident. According to the
Department, research programs "should reassess
protocols involving inhalation of hexamethonium
and, if necessary, consider temporarily
suspending the research in light of this
event." While study volunteers were warned that
hexamethonium could lower blood pressure and
cause dizziness, they likely were not told that
inhalation of the drug could cause death.
http//www.injuryboard.com/view.cfm/Article457
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Agents affecting the availability of acetylcholine
botulism toxin
protein exotoxin produced by gram-negative
anaerobe Clostridium botulinum
toxin is specific to strain A, B, Ca, Cb, D, E,
F, G.
cause food poisoning in humans
lethal dosehuman is 10-9mg/kg 50 mortality
binds to the presynaptic membrane of cholinergic
neurons preventing the exocytosis of
acetylcholine.

• treatments
• dystonia (involuntary rhythmic muscle spasms)
• excessive sweating
• headaches
• muscle spasticity
• pain
• crossed eyes
• blepharospasm

BOTOX - type A (1990) MYOBLOC - type B (2001)
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http//www.bbc.co.uk/science/hottopics/extremecosm
etics/botox.shtml
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agents affecting the availability of acetylcholine
black widow spider venom - a-latrotoxin
causes clumping of synaptic vesicles at
presynaptic membrane along with premature release
of acetylcholine
?-bungarotoxin
premature release of acetylcholine
180 amino acids multi-subunited
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agents affecting the availability of acetylcholine
anticholineesterases
Acetylcholineesterase is a serine esterase with
a mechanism of action like that of trypsin and
chymotrypsin
transesterification
hydrolysis
Xenobiotics which can interfere with this
mechanism will have a dramatic effect on anything
cholinergic. Acetylcholine will persist in the
synaptic area, eventually exhausting the receptor
response.
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agents affecting the availability of acetylcholine
anticholineesterases
organophosphates
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anticholinesterases
organophosphorous insecticides
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anticholinesterases
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Chemical Weapons Convention (CWC)
Organisation for the Prohibition of Chemical
Weapons (OPCW)

• destruction and prohibition of chemical weapons
  and facilities used to manufacture them
• restrictions on international trade in toxic
  chemical and precursors
• monitoring and verification

EXAMPLES nerve gases (sarin, tabun, etc.),
sulfur mustards, lewisites, nitrogen mustards,
saxitoxin, ricin
EXAMPLES BZ, arsenic trichloride, thiodiglycol,
pinacolyl alcohol, various phosphonates
EXAMPLES phosgene, cyanogen chloride, hydrogen
cyanide, thionyl chloride, phosphites
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anticholinesterases
GF is cyclohexylsarin.
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antidotes to anticholineesterases
pralidoxime (2-PAM)
symptomatic antidote - atropine
mode of action????
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Other oxime antidotes
obidoxime
HI - 6
SR - LD50/ED50 - safety ratio
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anticholinesterases
carbamates
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anticholinesterases
clinical anticholineesterases
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No loss of AP in nerve cells
loss of muscle tone
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anticholinesterases
MG
incidence - 5 in 100,000 10 develop in
childhood affects more women than men in the
40-year old age bracket
doomsday plant
Nigeria
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The Efik of Nigeria were the first to use the
Calabar bean, and believed it possessed the power
to reveal and destroy witches. The accused witch
was made to undergo a trial by ordeal, drinking
water to which had been added eight mashed ordeal
beans. The accused was then proclaimed innocent
only if he or she regurgitated the beans or
raised the right arm and survived. Since the
poison acted rapidly, the mouth of the accused
would often shake and the mucosal membranes would
discharge. In short, the witch died a horrible
death from paralytic asphyxia. Western settlers
captured by native people and forced to undergo
this ordeal soon learned that swallowing the
seeds whole prevented the poisons
release. Although outlawed throughout Africa,
the Calabar bean ordeal is astonishingly enough,
still practiced in some tribal rituals. The
beans were first introduced into England in the
year 1840. In 1846, the Edinburgh Botanical
Gardens planted the Calabar bean for study, where
the plant heartily grew into a strong perennial
creeper. However it wasnt until 1862, that
Thomas Fraser noticed the bean caused contraction
of the pupils, unlike belladonna and related
plants which dilated the pupils.