SYNAPSE, THE CONCEPT OF

ANTIDOTE, CURARE AND EXOTOXINS

POISONING

Presenter; MAIGE Sylvester

Group 6
Facilitaor; Dr. M. Njelekela
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 OBJECTIVES
At the end of this session we should be able
to:-
Define the synapses and types.
Explain how the impulse is transmitted
across the synapses.
Explain how curare and exotoxins poisoning
occurs and its clinical implications.
Explain the concept of antidote and its
clinical implications.
2
 Introduction
What is a synapse?
A synapse is the junction between 2 neurones.
There is a very narrow gap of about 20nm between
neurones called the synaptic cleft.
An action potential cannot cross the synaptic cleft,
so nerve impulses are carried by chemicals called
neurotransmitters.
The neurotransmitters are chemical substances
released from a nerve fibre and effecting the
transfer of an impulse to another nerve, muscle, etc
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 Types of Synapses-Chemical and
Electrical
In the chemical synapse the presynaptic neuron
releases a neurotransmitter which acts at the
postsynaptic neurone to excite, inhibit it, or modify its
sensitivity in some other way.
The electrical synapse consist gap junctions that
allow free movement of ions from one cell to the next
The membranes of the two cells actually touch,
allowing the AP to pass directly from one membrane
to the next.
They are very fast, but are quite rare, found mainly in
the heart and the eye.
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 Physiological Anatomy of the
Synapse
Pre-synaptic
neurone =
neurone sending
impulse
Post-synaptic
neurone =
neurone
receiving impulse

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Chemical Substances That Function
As Synaptic Transmitters
The neurotransmitters are made by the
pre-synaptic neurone and stored in
synaptic vesicles at the end of the axon.
The post-synaptic neurone has chemical-
gated ion channels in its membrane,
called neuroreceptors.
These have specific binding sites for the
neurotransmitters.

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 Chemical Substances That Function
As Synaptic Transmitters..
Small-Molecule, Rapidly Acting Transmitters
Are synthesized in the cytosol of the presynaptic
terminal and stored in the vesicles.
Each time an action potential reaches the
presynaptic terminal, a few vesicles at a time
release their transmitter into the synaptic cleft.
The most important of the small-molecule
transmitters includes;
Acetylcholine, Norepinephrine, Dopamine,
Serotonin, Gamma-aminobutyric acid (GABA),
Glycine, Glutamate and Nitric oxide (NO) 7
 Chemical Substances..
Neuropeptide, Slowly Acting Transmitters
or Growth Factors
They are synthesized as integral parts of
large-protein molecules by ribosomes in the
neuronal cell body, NOT in the cytosol.
The protein molecules then enter into the ER
of the cell body and then inside the Golgi
apparatus for final modification and
packaging into minute transmitter vesicles
that are released into the cytoplasm.
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 Chemical Substances..
These vesicles release their transmitter at the
neuronal terminals in response to AP in the
same manner as for small-molecule.
However, the vesicle is autolyzed and is not
reused.
Neuropeptides are 1000x or more times as
potent as the small-molecule trans. and they
produce a more prolonged effect
Eg; Thyrotropin-releasing hormone, Pituitary
peptides, Peptides that act on gut and brain,
Angiotensin II, Bradykinin Calcitonin etc.
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 How the impulse is transmitted
across the synaptic cleft
1. Action potential arrives at
the synaptic knob.

Vesicle storing
neurotransmitter

Ca2+
channel

Membrane receptor
for neurotransmitter

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 3. Ca2+ stimulates
vesicles to fuse
2. Depolarisation with membrane
opens Ca2+ channels
Ca2+ enters the
synaptic knob.

Ca2+ Ca2+ Ca2+ Ca2+

4. Exocytosis of
neurotransmitter
It diffuses 20nm across
the synaptic cleft

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5. Neurotransmitter
receptor sites on the
postsynaptic membrane
are ion channels.
They open when the
neurotransmitter binds

6. Localised
depolarisation as
ions leak in or out
of membrane. 12
 8. Neurotransmitter
destroyed by
enzymes in the cleft.
7. Action potential Stops signal being
generated which propagated.
travels down the
postsynaptic cell.
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 Action Of Transmitter On
Postsynaptic Neurone
The ion channels in the postsynaptic neuronal
membrane are cation or anion channels .
Cation channels allow sodium ions to pass
when opened, sometimes allow K+ and/or Ca2+
Anion channels allow mainly Cl- ions to pass.
A transmitter substance that opens cation
channels is called an excitatory transmitter
Conversely, transmitter substances that open
anion channels are called inhibitory transmitters
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Excitatory And Inhibitory Receptors In
The Postsynaptic Membrane
Excitation occurs by;
1)Opening of Na+ channels to allow positive
electrical charges to flow into the the
postsynaptic cell.
2)Depressed conduction through Cl- or K+
channels, or both.
3)Changes in the internal metabolism of the
postsynaptic neuron to increase the number of
excitatory receptors or decrease the number of
inhibitory receptors.
4)The opposite occurs in Inhibitory Receptors,
except that in (1) above Cl- enters.
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 Some Special Characteristics Of
Synaptic Transmission
1) Fatigue of Synaptic Transmission.
When excitatory synapses are repetitively
stimulated at a rapid rate, the number of
discharges by the postsynaptic neuron is at first
very great, then progressively reduced.
This is most important means by which the
excess excitability of the brain during an
epileptic seizure is finally subdued so that the
seizure ceases.
Fatigue involves mainly exhaustion or partial
exhaustion of the stores of transmitter
substance in the presynaptic terminals 16
 Special Characteristics..
2) Effect of Acidosis And Alkalosis on
Synaptic Transmission
Acidosis greatly depresses neuronal activity.
A fall in pH from 7.4 to below 7.0 usually
causes a comatose state.
Eg, in very severe diabetic or uremic
acidosis, coma virtually always develops.
In acidosis there will be high conc. of H+ in
the ECF so membranes will become
permeable to H+ ions.
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 Special Characteristics..
Effect of Acidosis On Synaptic
Transmission
As a result H+ conc. will increase in the ICF,
causing K+ to move out in exchange to H+
leading to hyperkalaemia.
Acidosis also impairs the activity of sodium
potassium pump.
High K+ conc. in the ECF decreases the
resting membrane potential and makes the
cells less excitable. 18
 Special Characteristics..
Effect of Alkalosis on Synaptic
Transmission
Alkalosis greatly increases neuronal
excitability.
Eg. a rise in arterial blood pH from the 7.4 to
7.8 to 8.0 often causes cerebral epileptic
seizures in predisposed persons.
Hypokalaemia, which occurs during alkalosis
increases the resting membrane potential
and makes the cells more excitable. 19
 Special Characteristics..
3) Effect of Hypoxia on Synaptic
Transmission.
Neuronal excitability is also highly dependent
on an adequate supply of oxygen.
When the brain's blood flow is temporarily
interrupted, within 3 to 7 seconds, the person
may becomes unconscious
4) Effect of Drugs on Synaptic Transmission.
Many drugs are known to increase the
excitability of neurons eg Caffeine (increased
alertness and deferral of fatigue), while others
are known to decrease excitability eg. glycine
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 Special Characteristics..
5) Synaptic Delay.
During transmission of a neuronal signal
from a presynaptic neuron to a
postsynaptic neuron, a certain amount of
time is consumed in the process.
This delay is about 0.5 millisecond.

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CURARE, EXOTOXINS POISONING AND
ANTIDOTES

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 Curare Poisoning
Curare is a potent neurotoxin.
Used as an arrow poison by some Indian
peoples of South America.
it is a natural extract obtained from tropical
American woody plants, especially
Chondrodendron tomentosum.
The principal chemicals of curare are
alkaloids that affect NMJ transmission.
Among the many alkaloids present in curare
preparations, the most important ones are
curarine and tubocurarine. 23
 Pathophysiology of curare
poisoning
The curare molecule mimics the
neurotransmitter Ach by binding to its
receptor at NMJ.
This prevents nerves from stimulating
muscle contraction.
The resulting paralysis onsets gradually,
because curare must compete for receptor
binding sites before occupying them.
Death from curare is caused by loss of the
ability to breathe as a result of paralysis.
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 Pathophysiology of curare
poisoning..
Typically the toxin kills only if it enters the
blood stream.
The amounts used to hunt animal are
easily broken down in the gut, making the
downed game safe for hunters and others
to eat.

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 Clinical Application Of Curare
Curare, usually in the form of D-tubocurare,
(Tubocurarine chloride) was the first muscle
relaxant to be used medically.
Nowadays, synthetic drugs such as
Pancuronium bromide with similar molecular
action are used.
It is also useful for treating the paralysis
caused by tetanus because the muscle
relaxant counters the contractions caused by
the tetanus toxin. 26
 Clinical Application Of
Curare..
Tubocurarine chloride can also be used
in various orthopaedic procedures such
as alignment of fractures and correction of
dislocations.
Antidotes for curare intoxication includes
anticholinesterase drugs like
edrophonium,neostigmine etc.
They reverse the action of curare at the
NMJ.
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 Pathophysiology Of Poisoning
By Exotoxins
Tetanus and Botulinum toxins inhibit
transmitter release, lowering transmitter
concentration in the synaptic cleft.
These toxins are produced by anaerobic soil
bacteria.
Botulinum poisoning usually occurs in people
who have eaten improperly preserved foods;
the toxin can be destroyed by heating
Tetanus poisoning occurs when an open
wound is exposed to the contaminated soil,
nails etc. 28
 Poisoning By Exotoxins
Both types of toxin are proteins which are
protease enzymes.
Botulinum toxins selectively attack and break
down proteins (synaptobrevin, syntaxin,
SNAP-25) required for docking of synaptic
vesicles with the presynaptic membrane.
Botulinum inhibits neuromuscular junctions &
other synapses.
Tetanus toxin inhibits CNS synapses that
release the inhibitory transmitters, glycine
and gamma-aminobutyric acid (GABA)
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Action Of Tetanus Toxin

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Tetanus And Botulinum Toxins
Compared:

Botulinum toxin (in very small local injections!) is

used to treat several clinical disorders with muscle
spasms 31
 Tetanus And Botulinum
Toxins : Antidotes
Prevention of tetanus achieved by;
(1) active immunization with toxoids;
(2) prophylactic use of antitoxin;
Treatment for botulism is done by administration of
Botulinum trivalent (A, B, E) antitoxin.
It acts by neutralising the toxins formed by type A,
type B, type E. Other Drugs (guanidine
hydrochloride, Fampridine)
It can arrest the progression of paralysis and
decrease the duration of paralysis and dependence
on mechanical ventilation. 32
 The Concept Of Antidotes
Definition; An antidote is a medicine taken
to counteract a particular poison.
The antidotes are specific in action and they
should only be given for a specific type of a
poison.
The antidote may be given to counteract the
effect of a Drug overdose, snake venom,
agricultural insectcides etc

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 Specific Example Of Poisoning
And Their Antidotes
1) Poisoning with Organophosphorus
insecticides: eg. parathion, malathion.
Widely used in agriculture
2) Poisoning with Organophosphorus nerve
gases: diisopropyl fluorophosphonate, sarin,
soman, tabun, agent VX .
Agents developed for chemical warfare
Similar to the insecticides, but more toxic to
humans
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 Specific Example Of Poisoning
And Their Antidotes..
The organophosphorus are Competitive
inhibitors of acetylcholinesterase.
Inhibit acetylcholinesterase in NMJs and
synapses (including the CNS).
The accumulation of acetylcholine results in
muscle twitching, glandular hypersecretion
cognitive and mood effects.
High doses cause seizures and death from
respiratory failure.
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 Specific Example Of Poisoning
And Their Antidotes..
Treatment of nerve agent poisoning at
present relies on two approaches.
In the first, an oxime eg. pralidoxime is
given to detach the agent from
cholinesterase, thus reactivating the
enzyme.
In the second, the muscarinic antagonist
atropine is used to stop the effects of
excessive acetylcholine action.
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 Snake Neurotoxins And Their
Antidotes
Alpha-bungarotoxin is a neurotoxin produced
by snakes like the banded krait, cobras,
mambas, and coral snakes.
Alpha-BTX is a highly toxic snake venom
alpha-neurotoxin that binds to acetylcholine
receptor (nAChR) at the NMJ, and is a
potent inhibitor of this receptor.
Snake venom antisera are the only specific
antidotes available for venomous snake
bites. 37
Thank you for listening!

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 References
1) Guyton& Hall; Textbook of Medical
Physiology 11th Edition pg 559-574
2) Jawetz, Melnick, & Adelberg's Medical
Microbiology 22nd Edition (2001) pg 230-
239
3) Dmitry M. L et al (2009); Specific
Membrane Binding of Neurotoxin II Can
Facilitate Its Delivery to Acetylcholine
Receptors. Biophys J. 2009 October 7;
97(7): 20892097.
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