Pharmacodynamics of Snake Venoms and Envenomation
by
Lee Moore
Introduction
This paper is not
intended as an all-inclusive presentation of all
components of snake venoms nor does it propose to
explain all the physiological processes involved in
snake envenomation.
Rather it is intended as a brief introduction and
description of the biochemical mechanisms involved
during snake envenomations in general. It attempts this
from an innovative and simplistic perspective.
It should be pointed out here, that the previously
established practice of classifying a venom as either
hematoxic or neurotoxic has proven to be flawed and
insufficient in defining the true nature of snake venoms
and toxins. Since the establishment of the
International Society on Toxinology and
publishing of its interdisciplinary journal of toxins,
TOXICON, there has been a source of
shared information that has helped to provide some
standardization. However, there is still a problem with
general classifications. Toxins are often termed
according to the emphasis of the study in which they are
identified. Cardiotoxins, as an example, can be a
cytotoxin that has proven to have considerable effects
on the cardiac muscle cells, or a Myotoxin that
specifically affects the heart. It may be that these
generalizations cannot be avoided or may even be
necessary since the effects of toxins are certainly
dependant on a number of factors exogenous and
endogenous to the physiology of the host. Toxins cannot
be expected, except under controlled situations, to
always react with the same effects. However with this
generalization of terms it is necessary to have a broad
knowledge of all the potential specifics.
Snake venoms
are composed of various collections of polypeptides.
These polypeptides are toxins that or either enzymes or
non-enzymatic polypeptides. The effects or actions of
these toxins are, on the most part, either by a means of
degradation of cells, tissues and/or intercellular bonds
or by a competitive inhibition blocking transmission of
acetylcholine. Exceptions to this is found in all
species belonging to the genus Dendroapsis, snakes known
as mambas.
Other venom
components have been identified including carbohydrates,
lipids, nucleoside and some metals. Magnesium, calcium,
and zinc are the most prevalent metals, copper has been
detected in some venoms. There are studies that suggest
that some of these co-constituents may play an active
role in the lethality of venoms. The purpose of this
paper is not to present validity to, or to dispute any
such finding. However, it is the opinion of this author,
that though there probably is validity in these findings
the importance of these substances to effect toxicity
would probably be academic, because such substances are
either endogenous to the host or indigenous, in some
way, to the envenomation itself.
Enzymes
Though most snake venoms have enzymes that act as toxic
constituents, all are composed of several enzymes. More
than 20 enzymes have been detected in snake venoms, and
12 are found in all venoms. The majority of toxic
effects of viperid and crotalid (pit vipers, including
rattlesnakes moccasins, etc.) envenomations are due to
enzymes collectively termed “proteases”. These are
actually hyrdolases that primarily act to breakdown
proteins, by hydrolysis and thus are proteolytic and
serve a digestive role. They are also the cause of most
of the local damage following envenomation. These
enzymes are further separated and classified according
to the mode or target site of their actions, for
instance endo - and exopeptidases. These target bonds in
the peptide chains that hold proteins together. One of
the enzymes that are present in all snake venom is
Hyalurondase. It is present in viperid, crotalid,
elapid and hydrophid venoms, as well as in most animal
venoms. Its effect can readily be observed following
envenomation as blood oozing from the bitten site. This
is the first good indication that can be observed,
following a bite, to determine if an envenomation has
occurred. The absence of this oozing is a possible
indication that no or little venom was injected.
Hyalurondase is known to have a “spreading action”. It
is the first enzyme to take action by facilitating other
venom components through tissues and into the
bloodstream. It greatly increasing permeability of
membranes, ruptures cellular walls and alters
coagulation. In a sense it acts as a “ vehicle” to
provide active transport for other toxic components.
It is not only the snake toxins itself that exerts toxic
effects, but also the products that are produced by the
digestive process of the enzymes. Such is the case
involving the phospholipases that produces lytic
products by cleaving membrane-bound phospholipids.
Another example of this involves L-Amino-acid oxidase,
which is another found in all snake venoms. It causes
the release of the powerful lytic chemical hydrogen
peroxide. Its toxic effect is by oxidation of cells.
In cases involving venoms that exerts their primary
toxic effects as a neurotoxin, affecting neuromuscular
processes, it is not enzymes, but other non–enzymatic
polypeptides that act as the primary lethal agent.
However, enzymes, always play an active role in
facilitating the spread of these non-enzymatic
polypeptides.
PROTEOLYTIC OR HEMOLYTIC?
Snake venom enzymes
are proteolytic and hemorrhagic toxins. These cause
hemorrhage by targeting fibrinogen converting it by
digestion into an unclottable substance or by directly
causing lysis of blood cells. Blood platelets and
Prothrombin are also sometimes affected leading to
coagulopathy of sorts and even hemorrhage. Ultimately
hypovolemia can result in any case. Constituents have
been found in snake venoms that have activating and
inactivating effects on nearly all aspects of
hemostasis. Some studies have indicated that some of
these hemorrhagic toxins may not be enzymatic in nature.
However, most are certainly enzymes. In contrast to
causing hemorrhage, some toxins has been found to act in
the same path as human endogenous clotting factors, but
in the cases of these exogenous agents there are no
controlled corresponding inhibitors. A notable example
is the Russell’s viper Daboia Russelli. Its
venom causes severe coagulopathy by preventing
coagulation then activating uninhibited coagulation.
Much research using this venom has already revealed uses
to further understand human clotting factors and control
coagulopathy disorders.
The method by which proteolytic toxins digest proteins
is not entirely different than what occurs during
hemolysis. In both cases there is lysis causing cellular
and tissue destruction by the some means of
degradation. The question, or rather an observation may
arise, what differentiates a proteolytic toxin as
opposed to a hemolytic one? Perhaps what actually
constitutes the difference is the level at which the
lytic damage is noted.
MYOTOXINS and
CARDIOTOXINS
Cytolytic or
Hemolytic?
Whereas
many, if not all, toxic venom enzymes can prove to be
toxic to muscle during envenomation there are also
toxins that have been determined as specific myotoxins.
These are basically cytotoxins that cause damage to
muscle cells. Many cardiotoxins are cytotoxins that have
been found to exert specific damage to cardio cells.
The toxin that is cytolytic is certainly also hemolytic.
A hemolytic or cytolytic toxin certainly has potential
as a myotoxin or cardiotoxin.
Neurotoxins
It has already been discussed that the lethality of some
snake venoms is not contributed to enzymes, but rather
to other polypeptides that are devoid of enzymatic
activity. There are also polypeptide neurotoxins termed
curare-mimetic toxins or postsynaptically
acting neurotoxins that blocks acetylcholine to
receptors at the neuromuscular junctions at the heart
side of the synapse. However, the greatest effects of
these toxins are generally exerted on respiratory
muscles. They interfere with the reception of
acetycholine on nicotinic receptors at the neuromuscular
junctions.
Presynaptic neurotoxins also have a similar end
effect on muscle contraction, as do the postsynaptic
neurotoxins, but take a different path that blocks the
transmissions of acetylcholine by prejunctional blocking
before the synapse. The nerve signal transmission, in
most cases is reduced or never reaches the receptor.
Three groups of presynaptic neurotoxins are known. The
Phospholipase A 2
(PLA 2-
toxins), the dendrotoxins and the fasciculins,
(anticholinesterase toxins) . The
later two groups are only found within the mamba,
dendropsis species. All elapid venoms, hydrophid, and
some crotalid and viperid share the group of PLA
2 –toxins.
The actions of most neurotoxins can be explained in
general as acting either in competitive inhibition,
targeting and blocking receptor sites or by preventing
release of acetylcholine. This results in muscular
paralysis. Though presynaptic and postsynaptic toxins
are devoid of substantial enzymatic activity, it should
be noted there are enzymes present in the venom that
aids in facilitating the spread of these toxins.
The dendrotoxins and fasciculins, contrary to blocking
the receptors or by reducing the release of
acetylcholine, as with all other neurotoxins, facilitate
release of acetylcholine and augment responses to nerve
stimulation in amplitude and duration. A note should be
added here that the content of mamba venom varies
between the four species. D. polylepis, D. viridis and
D. jamesonii also contain potent postsynaptic
neurotoxins, whereas, D. angusticeps does not. There
are other variations among the venoms of these snakes
and in all cases the overall toxicity is a result of a
synergistic characteristic between the different venom
constituents. For instance of D. augusticeps the
lethality of the whole venom is 5 to 15 times more toxic
than its most lethal component.
Summary
Though the natural primary purpose of
venom is primitive in nature, serving to secure prey and
for defense, more clues to understanding its agents and
reactions are more easily understood, when their
subsequent purposes are contemplated. The first of
these, which is relevant to securing of prey, is the
immobilization of its prey. It is here where complex
processes occur that prevent the ordinary physiological
functions that maintain homeostasis. The velocity at
which these agents reach the intended physiological
targets and accomplish their purpose is a subject that
evokes wonder. The processes and their results are
comparable to a lock or switch, that when turned either
prevents physiological processes by locking out
receptors or by unlocking and releasing agents that
results in a malfunction. The individual toxins work
together in a dynamic way to facilitate the processes
and functions in the whole venom. Further investigation
and understanding of these processes can provide a
wealth of information about ordinary physiological
processes and potential means of controlling them.
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