Basic Neurophysiology
As it is known nerve transmission
at the end receiving organ or structure such as a muscle fiber or a smooth
muscle cell or a glandular cell is mediated by chemicals molecules called
neurotransmitters. One of such neurotransmitter is acetylcholine. It is
the neurotransmitter of the junction (called also synapsis) between nerve
fibers of the Central Nervous System and muscles, involved in all body
motion and in respiratory muscles. Acetylcholine is also one of the neurotransmitters
between nerve fibers of the nervous system and smooth muscle cells of the
eye pupil, gastrointestinal tract, heart, and ureter and bladder, and gland
cells such as salivary glands and sweats glands. It is also one of the
neurotransmitter between nerve fibers of the nervous system. Acetylcholine
is one of the many neurotransmitters within the Central Nervous System.
Acetylcholine is the neurotransmitter between the Central Nervous System
nervous fibers and peripheral groups of nervous cells called ganglions
(which are part of the autonomic nervous system).
How does it work? Neurotransmitter
molecule is formed in the nerve ending expansion, and stored there. On
receiving the nerve impulse it is carried through the end wall of the expansion
(called pre-junction membrane or pre-synaptic membrane), cross the junction
(synapsis) and goes to install itself on the membrane of the receiving
cell (post-synaptic membrane). The installation on the post-synaptic membrane
is in particular places, called receptors, which are good only for that
particular molecule or any molecule of very similar structure. Just like
a key in the locker. By sitting on those receptors they elicit the response
(muscle contraction or secretion etc.). Just like a key in a locker, sometime
a key very similar to the right one can enter the locker but does not turn
the mechanism. Various chemical substances have structures very similar
to a variety of neurotransmitters, and have a variety of similar functions.
Like a similar key sometimes opens the locker, sometimes fits in to the
locker without opening it, sometime fits the locker without coming out,
so molecules of various type similar to neurotransmitters can in various
way adversely affect nerve impulse transmission at the junction (synapsis).
For instance, some snake venom behaves exactly so, they are a key similar
to acetylcholine, which fit in the post synaptic acetylcholine receptors.
However as an imperfect key does not work properly, and in just sitting
there do not let (inhibit) the normal neural transmission to work. In the
case of muscle neuromuscular junction, this causes paralysis of the muscle.
In the post junction membrane
of smooth cells and gland cells, the acetylcholine fit in receptors which
are slightly different from acetylcholine receptors present in the post
junction membrane of muscle cells. They are called with different names,
muscarinic receptors the first and nicotinic receptors the second. Conversely
different but similar molecules can, like a key in a locker, fit or not
fit in those receptors. This is one of the basic mechanism involved in
many pharmacologic use of chemical molecules (drugs) and or damaging activity
of other chemical molecules (poisons or toxins).
In the case of organophosphate
pesticides, or, which is the same, nerve agents, the poisonous molecules
do work in a different manner but within the same mechanism.
Now it becomes slight more
difficult: once our acetylcholine has installed itself on the acetylcholine
receptors in the post synaptic membrane, a stimulus is elicited in that
membrane and the muscle fiber contracts, or the gland cell secretes, and
so on. In order to prevent acetylcholine from continuously firing those
receptors there is an enzyme called acetyl cholinesterase whose job it
to degrade acetylcholine. This happens immediately after the stimulus is
carried through, in hundreds of one second. So the story goes like this:
acetylcholine is one of the chemical message used by the body to activate
neuronal responses, and acetylcholinesterase brings the message to an end
by destroying acetylcholine. The effect having being obtained, the receptor
is ready for a new stimulus. A nicely controlled biological loop.
Now, organophosphate pesticides and nerve agents inhibit the activity of acetylcholinesterase by chemically binding to it in a key central position This means the loop is not working. Now, with all these pesticides or nerve agents around there is continuous presence of acetylcholine activating the receptors; there is no-more the enzyme (acetyl cholinesterase) to bring it to an end. So the good doctor decides to reduce the levels of acetylcholine artificially. This is achieved in two way, one by "freeing" the enzyme and restoring its activity, which is done with drugs called collectively oximes. One other way is by adding inhibitors of acetylcholine receptors. Atropine is one such inhibitor. Unfortunately Atropine does fit only in the muscarinic type of receptors.
As said muscarinic receptor
is the name of the acetylcholine receptors in the smooth muscle cells (eye
pupil, gastrointestinal tract, ureter and bladder) and some glands (salivary
glands and sweat glands), while the name of the acetylcholine receptor
in the skeletal muscles is nicotinic receptor. To a different name does
correspond a slightly different molecular structure. Again just as in the
cases of similar keys some molecules, being similar to acetylcholine, can
fit in only one of the two types of receptors, some fit in the muscarinic
ones, some fit in the nicotinic ones, some in both.
Atropine is a muscarinic
antagonist, that is to say it attaches to the muscarinic receptor and prevents
acetylcholine from doing so. It "looks like" acetylcholine in some way,
that is why it binds to muscarinic receptors, only once attached it
does not activate the receptor. Overall it is a competitive inhibitor;
the more atropine you have the less acetylcholine can bind to the muscarinic
receptor. In other words Atropine inhibit acetylcholine at the muscarinic
receptor site. It is consequently a corrector, an antidote, to the damaging
effect of the nerve agents. In facts nerve agents cause increase activity
of acetylcholine, the increased activity of acetylcholine keeps on stimulating
disorderly the receptors, which keep on discharging signal. By occupying
the receptors but not stimulating them, Atropine counteract the activity
of nerve agent at the muscarinic receptor site.
Unfortunately Atropine is
not enough similar to acetylcholine to install on the nicotinic receptors,
is therefore ineffective in the skeletal muscles.
What about the neuromuscular
junction then? The nerve agents cause an excessive amount of acetylcholine
to be present and permanently in the nicotinic receptors, which therefore
keeps on firing. The muscle fibers keep on receiving order to contract,
contractions of overall fibers does not result in generalized contraction
of all muscles but rather in a generalized uncoordinated contraction of
single muscle fibers. There will be involuntary muscular twitching in all
part of the body, scattered muscular fasciculations and occasional muscle
cramps. All this picture is followed by generalized muscle weakness and
this situation on the respiratory muscle causes arrest of the ventilation
and death by lack of breathing and consequently lack of oxygen. In fact
opposite to smooth muscle cell, the skeletal muscle cannot contract continuously
and fatigue will supervene, causing the generalized weakness. To counteract
the effect of nerve agent the oximes (such as Pralidoxime -Pralidoxime
chloride, Protopam chloride, 2-PAMCl. Mark I Kit) are used. Oximes are
given IM or IV. The oximes break the bond between nerve agents and acetylcholinesterase,
freeing the enzyme and therefore restoring its activity. Therefore the
oximes are active everywhere, in the skeletal muscle (nicotinic receptors)
and in the glands and smooth muscles (muscarinic receptors). All these
informations are coming from oximes uses in organophosphate insecticide
poisoning.Oximes are not presently available in North Iraqi Kurdistan.
In addition to the action
of nerve agents on skeletal muscles and glands and smooth muscle cells,
there is also an action on the Central Nervous System -CNS- and particularly
a depressive effect on the respiratory center in the CNS. Atropine, which
is not effective on the muscle, is however effective in the Central Nervous
System where it does counteract the depressing activity on the respiratory
center. Unfortunately Atropine does not penetrate easily through the blood
brain barrier, and to have a central effect the dose must be somewhat higher
then in the periphery.
Oximes do not penetrate
blood brain barrier, or even much less so than Atropine. Even though they
are on theory acting everywhere because they free the acetylcholinesterase,
they do not reach the enzyme within the CNS. Atropine still needs to be
given.
Botulinum toxins act also
at the neuromuscular junction but with a different mechanism. The toxins
localize themselves at the nerve ending expansion and interfere with normal
extrusion through the presynaptic membrane of the small vesicles containing
the stored acetylcholine. In this way acetylcholine cannot be released
and go through the junction to install on the post synaptic receptor. The
neurotransmission is completely arrested.