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TOXIC EFFECTS OF
TERRESTRIAL ANIMAL
VENOMS AND POISONS
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Findlay E. Russell
Lepidoptera (Caterpillars, Moths, and Butterflies)
Formicidae (Ants)
Apidae (Bees)
Heteroptera (True Bugs)
PROPERTIES OF ANIMAL TOXINS
ARTHROPODS
ARACHNIDA
Scorpions
Spiders
Latrodectus Species (Widow Spiders)
Loxosceles Species (Brown or Violin Spiders)
Steatoda Species (Cobweb Spiders)
Cheiracanthium Species (Running Spiders)
Phidippus Species (Jumping Spiders)
Ticks
REPTILES
Lizards
Snakes
Snake Venoms
Enzymes
Polypeptides
Toxicology
Snakebite Treatment
CHILOPODA (CENTIPEDES)
ANTIVENOM
DIPLOPODA (MILLIPEDES)
INSECTA
the scorpions, although they do use their venom in defense. In the
fishes, such as the scorpionfishes and stonefishes, and in elasmobranches, such as the stingray, the venom apparatus is generally
used in the animal’s defense. There does not appear to be any evidence that it is employed in a food-getting capacity, nor would the
chemistry or pharmacology so indicate. Venoms used in an offensive posture are generally associated with the oral pole, as in the
snakes and spiders, while those used in a defensive function are
usually associated with the aboral pole or with spines, as in the
stingrays and scorpionfishes. The poisonous animals, on the other
hand, usually derive their toxins through the food chain, and as
such the poison is often a product of metabolism, sometimes concentrated as it passes through the food chain from one animal to
another.
Toxinologists generally separates the “venomous” animals from
those termed “poisonous.” The former are those animals capable
of producing a poison in a highly developed secretory gland or
group of cells and that can deliver their toxin during a biting or
stinging act. Poisonous animals, by contrast, are generally regarded
to be those whose tissues, either in part or in their entirety, are
toxic. These latter animals have no mechanism or structure for the
delivery of their poisons, and poisoning usually takes place through
ingestion (Russell, 1965). Venomous or poisonous animals are
found in every phylum, even the birds. For the most part, they are
widely distributed throughout the animal kingdom, from the unicellular protistan Alexandrium (Gonyaulax) to certain of the mammals, including the platypus and the short-tailed shrew. There are
at least four hundred species of snakes considered to be of a danger to humans. The number of venomous and poisonous arthropods must be countless, while toxic marine animals number approximately 1500 species and are found in almost every sea and
ocean (Halstead, 1965–1970; Russell, 1965, 1984; Russell and
Nagabhushanam, 1996).
An animal’s venom may have one or several functions. It may
play a role in offense, as in the capture and digestion of food, or
it may contribute to the animal’s defense, as in protection against
predators or aggressors. It can also serve both functions. In the
snake, the venom provides a food-getting objective. Its secondary
function is in its defensive stature. The presence of a toxic venom
in the snake is a superior modification to the animal’s speed, size,
concealment, or strength. In the venomous spiders, the toxin is used
to paralyze the prey before it extracts the hemolymph and body
fluids. The venom is not primarily designed to kill the prey, only
to immobilize the organism for feeding. The same can be said for
PROPERTIES OF ANIMAL TOXINS
The use to which an animal puts its toxin courses the nature of its
chemistry and pharmacology. Whether, in its evolution, the process
proceeds by trial and error or by some other means cannot be said.
Venoms contain both high- and low-molecular-weight proteins, including polypeptides and enzymes. There may also be amines,
lipids, steroids, aminopolysaccharides, quinones, glucosides, and
free amino acids as well as 5-hydroxytryptamine (5-HT), histamine, and other substances. Questions then arise as to why and
how these substances, most of which are common components of
most living tissues, are found in the venom glands, how they came
to concentrate there, and why the amounts are sufficient to make
them toxic or venomous. It has become apparent that venoms—
some snake venoms, for instance—may consist of more than a
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and size, facilitating absorption of excess interstitial fluid along
with macromolecules of a venom. Unlike blood flow, which is propelled by a powerful pump, namely the heart, lymph is propelled
for the most part by intrinsic segmental contractions of the large
and small trunks (lymphangions). With a well-developed intraluminal valve system, the volume of tissue, fluid, and venom components transported is enhanced by both increased rate and greater
stroke volume of the lymphangion micropumps (Witte and Witte,
1997).
The receptor sites appear to have highly variable degrees of
sensitivity. It is well known that the differences in the rate of metabolism of a venom at a receptor site can vary considerably in
mammals. The differences observed in effective amounts of venom
between human and laboratory animals does not necessarily reflect
any increased sensitivity on the part of the human’s target organs
but may be directly related to the differences in specific rates of
metabolism for the venom as well as the amount of the poison that
actually reaches that site. A toxin will produce its pharmacologic
effect when the quantity attains a critical minimum concentration
at the receptor site. In the case of such complex mixtures as snake
venoms, there may be several if not many receptor sites. There is
also considerable variability in the sensitivity of those sites for the
different components of a venom.
The site of action and metabolism of a venom is dependent
on its diffusion and partitioning along the gradient between the
plasma and the tissues where the components are deposited. In the
case of most snake venoms and fractions so far studied, the distribution is rather unequal, being affected by protein binding, variations in pH, and membrane permeability, among other factors. Once
the toxin reaches a particular site, its entry to that site is dependent upon the rate of blood flow into that tissue, the mass of the
structure, and the partition characteristics of the toxin between the
blood and that particular tissue. Some venom components have a
high affinity for certain tissues and exert their most deleterious effects at these sites. This observation has given rise to such terms
as neurotoxin, cardiotoxin, myotoxin, etc. In such cases the principal effector site may be the nerve, heart, or muscle, but evidence
is lacking that these same venoms or fractions do not exert additional deleterious effects, sometimes serious, on other if not most
tissues. Then, there is always the problem of how to label a fraction that affects the atrioventricular node. Is this neurologic or cardiovascular? It may seem unwise, in view of our meager knowledge, to claim an understanding of how a venom exerts its exact
deleterious effects. One way is to refer to its injurious property,
calling it, if we must, neurotoxic, cardiotoxic, or myotoxic, but
even those terms circumvent the science of being physiopharmacologically exact.
In addition to the receptor sites, a venom may also be metabolized in several or many different tissues. This is important in
considering the pharmacologic activity of a venom or venom fraction, for some components are metabolized distant to the receptor
site(s) and may never reach the primary receptor in a quantity sufficient to affect that site. The amount of a toxin that tissues can
metabolize without endangering the organisms may also vary. It
would be wise, as has been done in some venom studies, to examine tissue slices or homogenates and subcellular fractions of different tissues to determine their metabolic coefficient. In evaluating such data, however, it must be remembered that organs or
tissues may contain enzymes that catalyze a host of reactions, including deleterious ones. Enzymes that oxidize venom components
by oxygenase mechanisms are for the most part localized in the
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hundred proteins. Why are there so many? What synergistic and
antagonistic mechanisms may be involved, and what autopharmacological phenomena can take place?
One might ask: What is the relationship between the in vitro
and in vivo experiment? There is, of course a relationship, but we
are finding that putting a single venom component on an isolated
tissue preparation (often in far larger amounts than would ever
reach that activity site in vivo) does not give us the precise mechanism of action of the full venom; in fact, the data may mislead
us, particularly with respect to therapeutics. There is another unfortunate fact in studying the chemistry, pharmacology, and toxicology of venoms in that their structure and function are researched
by taking the venoms apart. This has two shortcomings: first, a destructive process is used in attempting to understand what must
have been a constructive one; second, the essential quality of the
venom may be destroyed before suitable acquaintance of the full
toxin has been made. Often, the technology becomes so exacting
that the end as to the venom’s function is lost sight of in our preoccupation with the means of the examination. Most venoms probably exert their effects on almost every cell and tissue, and their
principal pharmacologic properties are usually determined by the
amount of a fraction that accumulates at an activity site.
It seems advisable to suggest some general principles on what
occurs to a venoms as it passes through the numerous tissues in
order to reach an activity site or be metabolized or excreted. The
bioavailability of a venom is determined by its composition, molecular size, amount or concentration gradient, solubility, degree of
ionization, and the rate of blood flow into that tissue as well as the
properties of the engulfing surface itself. The venom can be absorbed by active or passive transport, facilitated diffusion, or even
pinocytosis, among other physiologic mechanisms. The role of surface integrins has not been determined for venom components.
In the case of active transport, the cell expends energy and
substrates may be accumulated intracellularly against a concentration gradient. In facilitated diffusion, it has been suggested that a
“carrier component” combines reversibly with the venom molecule
at the membrane’s outer surface, and that the carrier-substrate complex can then diffuse more rapidly across the membrane, releasing
the molecule (or toxin) to the membrane’s inner surface. For some
substances it is known that the process of facilitated diffusion is
highly selective, accepting only those components that have a relatively specific molecular configuration. There is some evidence
to suggest that some fractions of venoms are transported across a
membrane by pinocytosis—a process by which a cell engulfs particles or fluids by invaginating and forming a vesicle that later buds
off within the interior cell. The venom is then transmitted into the
vascular bed, sometimes directly or sometimes through lymphatic
channels. This may be determined by the molecular size of its components, by water-oil (or other) partition coefficients, or by some
other process causing its movement to the various receptor sites.
The role of the lymphatics and the characteristics in the transport and absorption of snake venom is a much neglected subject
in toxicology and toxinology. The lymph circulation not only carries surplus interstitial fluid produced by the venom but also transports the larger molecular components and other particulates back
to the bloodstream. Thus, the larger toxins of snake venoms, particularly those of Viperidae, probably enter the lymphatic network
preferentially and then transported to the central venous system in
the neck. Because lymphatic capillaries (i.e., initial lymphatics),
unlike blood capillaries, lack a basement membrane and have fibroelastic “anchoring filaments,” they can readily adjust their shape
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seen in one series of cases, 80 percent were found to be caused by
arthropods other than spiders or by other disease states (Russell
and Gertsch, 1983). The arthropods most frequently involved in
the misdiagnoses were ticks (including their embedded mouthparts), mites, bedbugs, fleas (infected flea bites), Lepidoptera insects, flies, vesicating beetles, water bugs, and various stinging Hymenoptera. Among the disease states that were confused with
spider or arthropod bites or stings were erythema chronicum migrans, erythema nodosum, periarteritis nodosum, pyroderma gangrenosum, kerion cell–mediated response to a fungus, StevensJohnson syndrome, toxic epidermal necrolysis, herpes simplex, and
purpura fulminans.
As with the snake, a spider or any other arthropod may bite
or sting and not eject venom. The author has seen many such cases.
Finally, some arthropod venom poisonings give rise to the symptoms and signs of an existing undiagnosed subclinical disease. The
problem of diverse disease states following bites or stings of various venomous animals has been recognized (Russell, 1979), and
when a case of poisoning appears to persist, the patient should be
reexamined for the possible presence of some undiagnosed disease.
In some cases, stings or bites may induce stress reactions that bring
the unrecognized disease to the surface.
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parenchymal cells of the liver, while other enzymes are found
somewhat unevenly distributed throughout many tissues. Again,
it should be remembered that these cell types can and do differ between human and other mammals, and particularly the lower
animals.
Once a venom component is metabolized or in some way altered, the end substance is excreted, principally through the kidneys. The intestines play a minor role, and what contribution the
lungs and biliary system may make has not been determined. Excretion may be complicated by the direct action of the venom on
the kidneys themselves, causing an inflammatory reaction that may
produce gaps between the endothelial fenestrae, very small pores,
so they are more permeable than skeletal muscle capillaries. Intestinal, salivary, and sweat gland capillaries also contain fenestrae. Indeed, the author has been impressed by the damage to the
kidneys in humans seen on postmortem examination following crotalid and viperid bites. Although no generalization concerning the
damage wrought by a snake venom on the organ systems of humans can be made (as compared with other mammals), the changes
in the kidneys would seem only secondary to those occurring in
the heart, and of course, the blood vessels (Russell, 1980a, 1980b,
1983). To sum up, applying a venom or venom fraction directly to
an isolated tissue preparation of the mouse or other small mammal
may provoke a quite different physiopharmacologic response, both
qualitatively and quantitatively than the same toxin produces in
vivo in the human.
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ARTHROPODS
There are more than a million species of arthropods, generally divided into 25 orders, of which at least 12 are of importance to humans from an economic standpoint. Medically, however, only about
10 orders are of significant venomous or poisonous importance.
These include the arachnids (scorpions, spiders, whipscorpions,
solpugids, mites, and ticks); the myriapods (centipedes and millipedes); the insects (water bugs, assassin bugs, and wheel bugs);
beetles (blister beetles); Lepidoptera (butterflies, moths, and caterpillars), and Hymenoptera (ants, bees, and wasps). In each of these
groups and perhaps in some others, there are additional creatures
that have been implicated in poisonings, but in most cases the
clinical evidence or chemical nature of the toxin appears to be relatively circumstantial to properly implicate their dangerousness to
humans. As noted by many authors, most arthropods do not have
fangs or stings long or strong enough to penetrate the human skin.
In treating the subject of venomous arthropods the writer has
not included those bites that, because of the trauma of their injury,
may be painful. I have also needed to exclude those creatures that
are vectors for certain bacterial, viral, or rickettsial disease and
those bites or stings that give rise to allergic reactions. There are
numerous texts and papers that deal with the general characteristics of venomous and poisonous arthropods. These inlcude those
of Minton (1968), Eberling (1975), Maretic and Lebez (1979),
Harwood and James (1979), Nutting (1984), and Smith (1997).
The number of deaths from arthropod stings and bites is not
known. Most countries do not keep records of the incidence of such
deaths or injuries. In Mexico, parts of Central and South America,
North Africa, and India, deaths from scorpion stings, for instance,
exceed several thousand a year. Spider bites probably do not account for more than 200 deaths a year worldwide. A common problem faced by physicians in suspected spider bites relates to the differential diagnosis. Of approximately 600 suspected spider bites
ARACHNIDA
Scorpions
The scorpions are said to be the oldest known terrestrial arthropods. There are at least a thousand species, among which the stings
of more than 75 can be considered of sufficient importance to warrant medical attention. Scorpions spend the daylight hours under
cover or in burrows. They emerge at night to ambush other arthropods or even small rodents, capture them with their pincers, sting
and paralyze them, or tear them apart and digest their body fluids.
Because they are carnivorous, the larger ones often feed on the
smaller. Scorpions live from 2 to 10 years, although there are reports of a 25-year life span. Some of the more important of these
species are noted in Table 26-1. In addition, members of the genera Pandinus, Hadrurus, Vejovis, Nebo, and some of the others are
capable of inflicting painful and often erythematous lesions. In the
United States the sting of Centruroides exilicauda (sculpturatus)
is dangerous, and in Mexico there were 20,352 deaths over two
9-year periods, chiefly in children less than 3 years of age. It has
been said that the total number of scorpion stings per year in
Mexico at present may be as high as 250,000, with perhaps 200
deaths. Working in Mexico in 1953, this writer estimated that there
were over 40,000 stings that year, of which 10,000 were treated or
reported. The total number of deaths appeared to be less than 1500.
The dangerous bark scorpion Centruroides exilicauda, so
called because of its preference for hiding under the loose bark of
trees or in dead trees or logs, often frequents human dwellings. Its
general color is straw to yellowish-brown or reddish-brown, and it
is often easily distinguishable from other scorpions in the same
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Table 26-1
Medically Important Scorpions
GENUS
DISTRIBUTION
Androctonus species
North Africa, Middle East,
Turkey
France and Spain to Middle
East and north Africa,
Mongolia, China
Africa, Middle East, central
Asia
North, Central, South
America
Central and southeast Asia
North Africa, Middle East,
Turkey
Turkey, India
Southern Africa
Central and South America
Buthus species
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Buthotus species
localized pain, swelling, tenderness, and mild parasthesia. Systemic
reactions are rare, although weakness, fever, and muscle fasciculations have been reported. These same findings have been reported
for the stings of the giant hairy scorpion, Hadrurus, another
member of the Vejovidae. Envenomations by some members of the
genus Centruroides are clinically the most important, particularly
in the western United States, where C. exilicauda is found. In children, their sting produces initial pain. However, some children do
not complain of pain and are unaware of the injury. The area becomes sensitive to touch, and merely pressing lightly over the injury will elicit an immediate retraction. Usually there is little or no
local swelling and only mild erythema. The child becomes tense
and restless and shows abnormal and random head and neck movements. Often the child will display roving eye movements. In their
review of Centruroides sculpturatus stings, Rimsza and coworkers
(1980) noted visual signs, including nystagmus roving eye and oculogyric movements, in 12 of 24 patients stung by this scorpion.
Loud noises, such as banging the examination table behind the
child’s back, often cause the patient to jump. Tachycardia is usually evident within 45 min as well as some hypertension. Although
this is not seen in children as early or as severely as in adults, it is
often present within an hour following the sting. Respiratory and
heart rates are increased, and by 90 min the child may appear quite
ill. Fasciculations may be seen over the face or large muscle masses,
and the child may complain of generalized weakness and display
some ataxia or motor weakness. Opisthotonos is not uncommon.
The respiratory distress may proceed to respiratory paralysis. Excessive salivation is often present and may further impair respiratory function. Slurring of speech may be present, and convulsions
may occur. If death does not occur, the child usually becomes
asymptomatic within 36 to 48 h.
In adults the clinical picture is somewhat similar, but there are
some differences. Almost all adults complain of immediate pain
after the sting, regardless of the Centruroides species involved.
Adults do not show the restlessness seen in children. Instead, they
are tense and anxious. They develop tachycardia and hypertension,
and respirations are increased. They may complain of difficulties
in focusing and swallowing, as may children. In some cases, there
is some general weakness and pain on moving the injured extremity. Convulsions are very rare, but ataxia and muscle incoordination may occur. Most adults are asymptomatic within 12 h but
may complain of generalized weakness for 24 h or more.
As noted elsewhere (Russell, 1996), a review of the therapy
for scorpion stings will provide a fascinating mixture of mythology, folklore, hunches, and a list of all sorts of therapeutic devices
from electroshock to mechanical compression. Measures such as
bed rest, positive-pressure breathing, mild sedation with diazepam
and antihypertensive drugs may be helpful when high blood pressure is a problem. An antivenom produced by Arizona State University for C. exilicauda stings is available and approved by the
state, but does not have the approval of the U.S. Food and Drug
Administration (FDA). An F(ab)2 polyvalent antivenom is produced in Mexico, but the former is preferred for U.S. species. Recently, the continuous infusion of midazolam has been used with
considerable success in serious C. exilicauda stings in Arizona
(Jones et al., 1988).
Centruroides species
Heterometrus species
Leiurus species
Mesobuthus species
Parabuthus species
Tityus species
habitat by its long, thin telson, or tail, and its thin pedipalps, or
pincerlike claws. Adults of this genus show a considerable difference in length. Centruroides exilicauda in the southwestern United
States and adjacent Mexico reaches a length of approximately 5.5
cm, while Centruroides vittatus of the Gulf states and adjacent
Mexico is generally slightly larger. Centruroides suffusus, a particularly dangerous Mexican species, may attain a length of 9 cm,
but Centruroides noxius, another important species, seldom exceeds 5 cm in length. Excellent reviews on scorpions have been
provided by Keegan (1980) and Polis (1990).
Many scorpion venoms contain low-molecular-weight proteins, peptides, amino acids, nucleotides, and salts, among other
components. The neurotoxic fractions are generally classified on
the basis of their molecular size, the short-chain toxins being composed of 30 to 40 amino acid residues with three or four disulfide
bonds and appear to affect potassium or chloride channels; while
the long-chain toxins have 60 to 70 amino acid residues with four
disulfide bonds and affect mainly the sodium channels. These particular toxins may have an effect on both voltage-dependent channels. The amino acid content is known for more than 90 species,
and there appears to be a high degree of cysteines in most of these
venoms. The toxins can selectively bind to a specific channel of
excitable cells, thus impairing the initial depolarization of the action potential in the nerve and muscle that results in their neurotoxicity. It appears that the way that some scorpion venoms differently affect mammalian, as opposed to insect tissues is related
to the structural basis of the gates in the two organisms. Not all
scorpions, however, have fractions that affect neuromuscular transmission. The venoms of most scorpions may be deleterious to other
arthropods, but they exert no significant systemic effects on humans. The American scorpion Vejovis spinigerus has no effect on
mammalian neurotransmission, reflex discharge, or antidromic inhibition, but at high doses it can provoke systemic arterial, venous,
and cisternal changes in mammals (Russell, 1968).
The symptoms and signs of scorpion envenomation differ considerably depending on the species. In the United States, the most
common offenders are members of the family Vejovidae, generally
found in the southwestern and western states as well as in Mexico,
Central America, and South America. Their sting gives rise to
Spiders
Of the 30,000 or so species, at least 200 have been implicated in
significant bites on humans. Some of the more medically impor-
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Tegenaria. Whether native or imported, all have all been implicated
in bites on humans in the United States.
Spider venoms are very complex and have been studied extensively, even as sources for new drugs (Coombs, 1992). From a
neuroactive standpoint, the widow and grass spiders, with their neurotranmitter release and channel-affecting properties; the jumping
spiders, with their Ca2 –channel blocking activity; and the argiope
and orb spinners, with their glutamate and Ca2 –channel blocking activities appear to show much promise as tools in studying
neurologic phenomena and perhaps for clinical use.
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tant of these spiders are noted in Table 26-2. Spiders are predaceous, polyphagous arachnids that generally feed on insects or
other arthropods. A more complete review of spider bites can be
found in the excellent work of Kaston (1978), Maretic and Lebez
(1979), Gertsch (1979), and the lesser contributions of Southcott
(1976) and Russell and Gertsch (1983). It is not possible to describe the chemistry, pharmacology, or immunology of the hundreds (perhaps thousands) of spider venoms that are toxic. Discussed here are only a few that appear to be clinically more
important in the United States. There are, however, bites by species
of Pheostica, Pamphobeteus, Bothriocyrtum, Ummidia, Phoneutria, Cupiennius, Lycosa, Heteropoda, Misumenoides, Liocranoides, Neoscona, Araneus, Argiope, Peucetia, Agelenopsis, and
Latrodectus Species (Widow Spiders) In the United States,
these spiders are commonly known as the black widow, brown
Table 26-2
Genera of Spiders for Which Significant Bites on Humans are Known
GENUS
FAMILY
COMMON NAME
DISTRIBUTION
Agelenopsis
Aganippe species
Aphonopelma species
Araneus species
Arbanitis species
Argiope species
Atrax species
Bothriocyrtum species
Cheiracanthium species
Cupiennius species
Drassodes species
Dyarcyops [Misgolas]
Dysdera
Elassoctenus [Diallomus]
Filistata species
Harpactirella species
Heteropoda species
Isopoda species
Ixeuticus [Badumna]
Lampona species
Latrodectus species
Liocranoides species
Loxosceles species
Agelenidae
Idiopidae
Theraphosidiae
Araneidae
Idiopidae
Araneidae
Hexathelidae
Ctenizidae
Miturgidae
Ctenidae
Gnaphosidae
Idiopidae
Dysderidae
Zordae
Filistatidae
Theraphosidae
Sparassidae
Sparassidae
Desidae
Lamponidae
Theridiidae
Tengellidae
Loxoscelidae
Grass spider
Trap-door spider
Tarantula
Orbweaver
Trap-door spider
Argiope
Funnel-web spider
Trap-door spider
Running spider
Banana spider
Running spider
Trap-door spider
Dysderid
Ctenid
Hackled-band spider
Trap-door spider
Giant crab spider
Giant crab spider
Amaurobiid
White-tailed spider
Widow spider
Running spider
Brown or violin spider
Lycosa species
Missulena species
Misumenoides species
Miturga species
Mopsus species
Neoscona species
Olios species
Pamphobeteus species
Peucetia species
Phidippus species
Phoneutria species
Selenocosmia species
Steatoda species
Tegenaria
Ummidia
Lycosoidae
Actinopodidae
Thomisidae
Miturgidae
Salticidae
Araneidae
Sparassidae
Theraphosidae
Oxyopidae
Salticidae
Ctenidae
Theraphosidae
Theridiidae
Agelenidae
Ctenizidae
Wolf spider
Trap-door spider
Crab spider
Running spider
Jumping spider
Orbweaver
Giant crab spider
Tarantula
Green lynx spider
Jumping spider
Hunting spider
Tarantula
False black widow
Funnel-web spider
Trap-door spider
North America
Australia
North America
Worldwide
Australia, East Indies
Worldwide
Australia
California
Europe, north Africa, Orient, North America
Central America
Worldwide
Australia
Eastern hemisphere, Americas
Australia
Temperate and tropical worldwide
South Africa
East Indies, tropical Asia, south Florida
Australia, East Indies
New Zealand, southern California
Australia, New Zealand
Temperate and tropical regions worldwide
Appalachia
Americas, Africa, Europe, eastern
Asia, Pacific Islands
Worldwide
Australia
North and South America
Australia
Australia
Worldwide
North and South America
South America
Worldwide
North and South America
Central and South America
East Indies, India, Australia, tropical Africa
Worldwide
Worldwide
North and South America
SOURCE:
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hypertensive crises may require intravenous nitroprusside. The use
of antivenom (antivenin, L. mactans) should be restricted to more
severe cases and when other measures have proved unsuccessful.
One ampule administered intravenously is usually sufficient. In patients who are under 16 or over 60 years, have any history of hypertension or hypertensive heart disease, or who show significant
symptoms and signs, the use of antivenom seems warranted; it also
is appropriate in cases involving pregnancy.
Loxosceles Species (Brown or Violin Spiders) These primitive
spiders are variously known in North America as the fiddle-back
spider or the brown recluse. There are over 100 species of
Loxosceles. Twenty of these species range from temperate South
Africa northward through the tropics into the Mediterranean region
and southern Europe. Another 84 species are known from North,
Central, and South America and the West Indies. The most widely
distributed is Loxosceles rufescens, the so-called cosmopolitan
species. It is found in the Mediterranean area, southern Russia,
most of north Africa including the Azores, Madagascar, the Near
East, Asia from India to southern China and Japan, parts of
Malaysia and Australia, some islands of the Pacific, and North
America. Loxosceles laeta is mostly South American, but it has
been introduced into Central America; small areas in Cambridge,
Massachusetts; Sierra Madre and Alhambra, California; and the zoology building of the University of Helsinki. The abdomen of these
spiders varies in color from grayish through orange and reddishbrown to blackish and is distinct from the pale yellow to reddishbrown background of the cephalothorax. This spider has six eyes
grouped in three dyads. Females average 8 to 12 mm in body length,
whereas males average 6 to 10 mm. Both males and females are
venomous. The most important species in the United States are
Loxosceles reclusa (brown recluse spider), Loxosceles deserta
(desert violin spider), and Loxosceles arizonica (Arizona violin
spider).
The chemistry and toxicology of Loxosceles venom were first
described by Schenone and Suarez (1978). Early work indicated
that the amount of venom protein per spider was about 68 mg. Although the venom is said to contain phospholipase, protease, esterase, collagenase, hyaluronidase, deoxyribonuclease, ribonuclease, dipeptides, dermanecrosis factor 33, dermonecrosis factor 37,
the most important factor is sphingomyelinase D. The relationship
between these various fractions is not clear, but most recent works
treat with the sphingomyelinase D. In Loxosceles intermedia a the
toxic effects appear to be associated with a 35-kDa protein (1735)
which demonstrates a complement-dependent hemolytic activity
and a dermonecrotic-inducing factor (Andrade et al., 1998).
31
P-Nuclear magnetic resonance assay of the four bands representing proteins, measuring 34 kDa in the venom, produced three
proteins with sphingomyelinase D activity (Merchant et al., 1998).
An endotoxemic-like shock, showing eosinophilic material in the
proximal and distal tubules and tubular necrosis, were the most
common histopathologic findings, preceded in mice by prostration,
acute cachexia, hypothermia, neurologic changes, and hemoglobinuria (Tambourgi et al., 1998). In Brazil, the sandwich-type
enzyme-linked immunosorbent assay (ELISA) for the detection of
venom antigens for L. intermedia in both animal and human
envenomations has been shown to be a useful diagnostic procedure
(Chavez-Olortegui et al., 1998). The venom has coagulation and
vasoconstriction properties. It causes selective damage to the vascular endothelium. There are adhesions of neutrophils to the capillary wall with sequestration and activation of passing neutrophils
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widow, or red-legged spider. They, however, have many other common names in English: hourglass, poison lady, deadly spider, redbottom spider, T-spider, gray lady spider, and shoebutton spider.
Widow spiders are found almost circumglobally in all continents
with temperate or tropical climates. In the United States, there are
at least five species, including the native L. mactans, L. bishopi,
L. variolus, L. hesperus, and the imported L. geometricus. Although
both male and female widow spiders are venomous, only the female has fangs large and strong enough to penetrate the human
skin. Mature L. mactans females range in body length from 10 to
18 mm, whereas males range from 3 to 5 mm. These spiders have
a globose abdomen varying in color from gray to brown to black,
depending on the species. In the black widow, the abdomen is shiny
black with a red hourglass or red spots and sometimes white spots
on the venter.
Through the years, one of the difficulties in determining the
composition of spider venoms, particularly that of Latrodectus spp.,
has been the procedure of grinding up the venom glands and preparing a homogenate of the glands and then attributing the chemistry
or toxicology to that of the actual venom. The manifestations of
the poisoning from the glands do not reflect those found in the in
vivo state. A family of high-molecular-weight proteins, latrotoxins, have been described in Latrodectus venoms. These are proteins of about 1000 amino acid residues (Grishin, 1999). Alphalatrotoxin is a presynaptic toxin which is said to exert toxic effects
on the vertebrate central nervous system in depolarizing neurons
by increasing [Ca2]i and by stimulating uncontrolled proteins described in Latrodectus venom. These are proteins of about 1000
amino acid residues (Grishin, 1999). Alpha-latrotoxin is a presynaptic toxin that is said to exert its toxic effects on the vertebrate
central nervous system in depolarizing neurons by increasing
[Ca2]i, and by exocytosis of neurotransmitters from nerve terminals (Holz and Habener, 1998). Along with the known GTP-binding
protein-coupled receptors, five latroinsectotoxins affecting neurotransmitter release from the presynaptic endings of insects and one
latrocrustatoxin have been isolated, and a alpha-latrotoxin preparation showed a low-molecular-weight protein structurally related
to crustacean hyperglycemic hormones (Greshin, 1998). By thinlayer chromatography (TLC) on silica gel, it was shown that
the venom kininase was a thiol endopeptidase (Akhunov et al.,
1996).
Clinical Problem Bites by the black widow are described as sharp
and pinprick-like, followed by a dull, occasionally numbing pain
in the affected extremity and by pain and cramps in one or several
of the large muscle masses. Rarely is there any local skin reaction
except during the first 60 min following the bite, but piloerection
in the bite area is sometimes seen. Muscle fasciculations frequently
can be seen within 30 min of the bite. Sweating is common, and
the patient may complain of weakness and pain in the regional
lymph nodes, which are often tender on palpation and occasionally are enlarged; lymphadenitis is frequently observed. Pain in the
low back, thighs, or abdomen is a common complaint, and rigidity of the abdominal muscles is seen in most cases in which envenomation has been severe. Severe paroxysmal muscle cramps
may occur, and arthralgia has been reported. Hypertension is a
common finding, particularly in the elderly after moderate to severe envenomations. Blood studies are usually normal.
There is no effective first-aid treatment. In most cases, intravenous calcium gluconate will relieve muscle pain, but this may
have to be repeated at 4- to 6-h intervals for optimum effect. Muscle relaxants such as methocarbamol 5 to 10 mg can be used. Acute
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venomation directed to the author in 1961 was thought to be caused
by L. mactans. The female of S. grossa differs from L. mactans
and L. hesperus in having a purplish-brown abdomen rather than
a black one. It is less shiny, and its abdomen is more oval than
round. It may have pale yellow or whitish markings on the dorsum
of the abdomen, and no markings on the venter. The abdomen of
some species is orange, brown, or chestnut in color and often bears
a light band across the anterior dorsum.
Cavalieri et al. (1987) state that the venom of Steatoda paykulliana had little effect on guinea pigs and no proteolytic activity
was noted, but high concentrations of the venom stimulated release
of transmitter substances similar to Latrodectus venom. A highmolecular-weight protein was toxic to houseflies. The venom is
said to form ionic channels permeable for bi- and monovalent
cations. It was found that the living time in the open state depended
on the membrane potential (Sokolov et al., 1984). According to
Maretić and Lebez (1979), S. paykulliana venom gives “strong motor unrest, clonic cramps, exhaustion, ataxia and then paralysis in
guinea pigs.” Bites by S. grossa or Steatoda fulva in the United
States have been followed by local pain, often severe; induration;
pruritus; and the occasional breakdown of tissue at the bite site.
Warrell et al. (1991) report a bite by Steatoda nobilis with unpleasant local and systemic “symptoms,” but whether the envenomation can be termed “neurotoxic” in humans remains questionable. In none of the seven S. grossa cases seen by the writer was
there any strong evidence of neurotoxicity. Perhaps there is a significant difference in the venoms of the various species. Wounds
should be debrided and covered, and signs should be treated symptomatically.
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by the perturbed endothelial cells (Patel et al., 1994). When the
venom is injected into mammals, it produces, in addition to the local tissue reaction, varying degrees of thrombocytopenia, some intravascular hemolysis, and hemolytic anemia.
Clinical Problem The bite of this spider produces about the same
degree of pain as does the sting of an ant, but sometimes the patient may be unaware of the bite. In most cases, a local burning
sensation, which may last for 30 to 60 min, develops around the
injury. Pruritus over the area often occurs, and the area becomes
red, with a small blanched area surrounding the reddened bite site.
Skin temperature usually is elevated over the lesion area. The reddened area enlarges and becomes purplish during the subsequent
1 to 8 h. It often becomes irregular in shape, and as time passes,
hemorrhages may develop throughout the area. A small bleb or
vesicle forms at the bite site and increases in size. It subsequently
ruptures and a pustule forms. The red hemorrhagic area continues
to enlarge, as does the pustule. The whole area may become swollen
and painful, and lymphadenopathy is common. During the early
stages the lesion often takes on a bull’s-eye appearance, with a central white vesicle surrounded by the reddened area and ringed by
a whitish or bluish border. The central pustule ruptures, and necrosis to various depths can be visualized. Not all bites, however, take
this course, some producing no more than localized pain, slight
redness, and minimal swelling (Russell, 1996).
In serious bites, the lesion can measure 8 by 10 cm with severe necrosis invading muscle tissue. On the face, large lesions resulting in extensive tissue destruction and requiring subsequent
plastic surgery sometimes are seen after bites by L. laeta in South
America. Systemic symptoms and signs include fever, malaise,
stomach cramps, nausea and vomiting, jaundice, spleen enlargement, hemolysis, hematuria, and thrombocytopenia. Fatal cases,
while rare, usually are preceded by intravascular hemolysis,
hemolytic anemia, thrombocytopenia, hemoglobinuria, and renal
failure. There have been no deaths in the United States from the
bites of this spider, contrary to reports in the media.
There are no first-aid measures of value. In fact, all first-aid
procedures should be avoided, as the natural appearance of the lesion is most important in determining the diagnosis. A cube of ice
may be placed on the wound. At one time, excision of the bite area
with ample margins was advised when this could be done within
an hour or so of the bite and when Loxosceles was definitely implicated. The value of steroids has been questioned. This writer,
however, has had seemingly good results with steroids following
bites by L. deserta, L. arizonica, and L. russelli. The patient should
be placed on a corticosteroid such as intramuscular dexamethasone, 4 mg every 6 h during the acute phase. Subsequent doses
were determined by clinical judgment, followed by decremental
doses over a 4-day period. Antihistamines are of questionable
value. The use of dapsone was suggested by King and Rees (1983).
The results have been encouraging, but care must be exercised with
this drug. If skin grafting becomes necessary, the procedure is best
deferred for 4 to 6 weeks after the injury. Systemic manifestations
should be treated symptomatically. Antivenom is not commercially
available but has been used in Tennessee (King, personal correspondence, 1990).
Steatoda Species The cobweb spiders, Steatoda spp., are variously known as the false black widow, combfooted, or cupboard
spiders. They are thought to have reached the Americas through
trading sources. These spiders are often mistaken for black widow
spiders, and indeed the first clinical case of Steatoda grossa en-
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Cheiracanthium Species (Running Spiders) The 160 species of
this genus have an almost circumglobal distribution, although only
four or five species have been implicated in bites on humans.
Maretić and Lebez (1979) named Cheiracanthium punctorium,
Cheiracanthium inclusum, Cheiracanthium mildei, and Cheiracanthium diversum as the spiders most often implicated in envenomations. In Japan, however, Cheiracanthium japonicum is a common biting spider. The abdomen is convex and egg-shaped and
varies in color from yellow, green, or greenish-white to reddishbrown; the cephalothorax is usually slightly darker than the
abdomen. The chelicerae are strong, and the legs are long, hairy,
and delicate. The spider ranges in length from 7 to 16 mm. Like
Phidippus but even more so, Cheiracanthium tends to be tenacious
and sometimes must be removed from the bite area. For that reason there is a high degree of identification following the bite of
these spiders. The most toxic fraction of the venom is said to be a
protein of 60 kDa, and the venom is high in norepinephrine and
serotonin.
The author’s experiences with seven bites by C. inclusum have
been very similar; the following description is based on those experiences. The patient usually describes the bite as sharp and
painful, with the pain increasing during the first 30 to 45 h. The
patient complains of dull pain over the injured part. A reddened
wheal with a hyperemic border develops. Small petechiae may appear near the center of the wheal. Skin temperature over the lesion
is often elevated, but body temperature is usually normal. Lymphadenitis and lymphadenopathy may develop. In Japan, C. japonicum produces more severe manifestations than we have seen with
the American or European species. These include severe local pain,
nausea and vomiting, headache, chest discomfort, severe pruritus,
and shock in addition to the local findings.
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Ticks
Respiration is affected and acetylcholine release is reduced, while
sensitivity at the neuromuscular junction is affected. Conduction
in motor fibers is said to be affected, with a functional deficiency
in afferent fibers. It has been suggested that in Dermacentor andersoni paralysis, the paralysis represents lower motor neuron injury and irritation of the posterior root of the spinal cord (Amese
and Lyday, 1939), while Rose (1954) has provided evidence that
the block is at the neuromuscular junction. It must be concluded
that the exact mechanism of the paralysis has yet to be determined.
Clinical Problem Except for some species, tick bites are often
not felt; the first evidence of envenomation may not appear until
several days later, when small macules develop. The macules are
3 to 4 mm in diameter and surrounded by erythema and swelling,
often displaying a hyperemic halo. The patient often complains of
difficulty with gait, followed by paresis and eventually locomotor
paresis and paralysis. Problems in speech and respiration may ensue and lead to respiratory paralysis if the tick is not removed.
Since the tick is often in the hair, it may remain unseen, thus confusing the differential diagnosis. Removal of the tick usually results in a rapid and complete recovery, although regression of paralysis may resolve slowly.
It seems probable that the ticks that cause the paralysis in humans and domestic animals may be the same, and that it is the
length of the exposure to the feeding tick that determines the degree of poisoning. Obviously, the first signs of poisoning are less
likely to be observed in cattle, sheep, dogs, and cats than in humans; as for symptoms (what the patient tells the physician), such
reports are not likely to be made. Treatment consists of removal of
the tick, using a formamidine derivative or petroleum product,
washing with soap and water, and treating specifically for the paralysis or other manifestation. It should be pointed out, again, that
these comments are specific only for tick venom poisoning and not
for allergic reactions, transmission of disease states, or other complications of tick bites.
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Phidippus Species (Jumping Spiders) These spiders, variously
known as crab spiders and eyebrow spiders, are usually less than
20 mm in length and have a somewhat elevated, rectangular
cephalothorax that tends to blunt anteriorly. The abdomen is often
oval or elongated. There is a great deal of variation in the color of
these spiders. In the female, the cephalothorax may be black,
brown, red, orange, or yellowish-orange and the abdomen tends to
be slightly lighter in color. In most species there are various white,
yellow, orange, or red spots or markings on the dorsum of the abdomen. These spiders are thought to have the sharpest of vision,
thus their hunting excellence. They have four large eyes on the face
and four smaller eyes on the dorsum of the head. The larger pair
of eyes on the face apparently serve for the sharpest vision.
A computer-aided key based on electromorph patterns for five
enzyme systems has been developed to determine specific species
of Phidippus. Digitized, and the gels graphed, the system provides
a ready identification of seven species of the spider (Terranova and
Roach, 1989). In their comprehensive study of the venom of 26
spider species belonging to 15 families, it was found that the toxic
effect of the venom was dramatic with respect to its cytotoxic effect on cultured cells, where there was a dramatic, instantaneous
disruption of cell membranes, resulting in the collapse of the neuroblastoma cells (Cohen and Quistad, 1998).
The bite of this spider produces a sharp pinprick of pain, and
the area immediately around the wound may become painful and
tender. The pain usually lasts 5 to 10 min. An erythematous wheal
slowly develops. In cases seen by the author, the wheal measured
2 to 5 cm in diameter. A dull, sometimes throbbing pain may subsequently develop over the injured part, but it rarely requires attention. A small vesicle may form at the bite site. Around this is
an irregular, slightly hyperemic area, which in turn may be surrounded by a blanched region that is tender to touch and pressure.
Generally, there is only mild lymphadenitis. Swelling of the part
may be diffuse and is often accompanied by pruritus. The symptoms and signs usually abate within 48 h. There is no specific treatment for the bite of this spider (Russell, 1970).
Tick paralysis is caused by the saliva of certain ticks of the families Ixodidae and Argasidae and perhaps others. An excellent review on the subject has been published by Gregson (1973), while
a more recent, shorter review is that of Smith (1997). Tick paralysis is known for both domestic animals and humans, being noted
in humans since 1912, although it was known to the American
Indians as pajaroella, due to Ornithodoros corisceus, long before
that time. There are said to be at least 60 species of ticks that have
been implicated in paralysis-producing disorders. With respect to
tick paralysis rather than tick toxicosis, one must consider the rickettsial, spirochetal, and microbacterial organisms transmitted by
ticks (or mites) that cause neurologic disorders similar to those produced by the organism’s saliva. Among the diseases due to organisms transmitted by ticks are Lyme disease, Rocky Mountain spotted fever, babesiosis, leptospirosis, Q fever, ehrlichiosis, typhus,
tick-borne encephalitis, and others.
The saliva of Ixodes holocyclus appears to have been most often studied and has yielded a number of substances that may cause
paralysis and, at high doses, death. Peak paralytic activity was
found between 60 to 100 kDa, and a lethal nonparalytic fraction
was found at 20 kDa. In Argas paralysis, the action appears to be
directed toward polyneuropathy, with only slight afferent pathways.
CHILOPODA (CENTIPEDES)
These elongated, many-segmented brownish-yellow arthropods are
found worldwide. With a pair of walking legs on most segments,
they are fast-moving, secretive, and nocturnal. They feed on other
arthropods and even small vertebrates and birds; they are cannibalistic. The first pair of legs behind the head are modified into
poison jaws or maxillipeds. Centipedes range in length from 3 to
almost 300 mm. In the United States, the prevalent biting genus is
a Scolopendra species. The venom is concentrated within the intracellular granules, discharged into vacuoles of the cytoplasm of
the secretory cells, and moved by exocytosis into the lumen of the
gland; from thence ducts carry the venom to the jaws (Ménez et
al., 1990).
The venoms of centipedes contain high-molecular-weight proteins, proteinases and esterases, 5-hydroxytrptamine, histamine,
lipids, and polysaccharides. In humans, such a venom produces
cardiovascular changes and changes associated with acetylcholine
release. It produces immediate bleeding, redness, and swelling of-
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may be derived from their ingestion of noxious plants, which are
then metabolized. Earlier studies showed that the toxic material
contained aristolochic acids, cardenolides, and histamine among
other substances. In recent studies, fibrinolytic activity has been
found at 16 and 18 kDa (isoelectric point of 8.5); coagulation defects such as prolonged prothrombin and partial thromboplastin
times have been detected, and decreases in fibrinogen and plasminogen have been noted. It is thought that the hemorrhagic syndrome cannot be classified as being either totally fibrinolytic or a
syndrome such as disseminated intravascular coagulopathy; it is
also held that the venom has urkinase activity (Kawamoto and
Kumada, 1984).
In some parts of the world the stings of several species of Lepidoptera give rise to a bleeding diasthesis, often severe and sometimes fatal. In the United States, envenomation by members of the
family Saturniidae, the buck moths, the grapeleaf skeletonizer
(family Zygaenidae), the puss moth (family Megalopygie), and the
browntailed moth (Euproctis species) generally gives rise to little
more than immediate localized itching and pain, usually described
as burning, followed in some cases by urticaria, edema, and occasionally fever. In the more severe cases abroad—often due to Megalopygidae, Dioptidae, Automeris, and Hermileucinae species—
there is localized pain as well as papules (sometimes hemorrhagic)
and hematomas; on occasion there may also be headache, nausea,
vomiting, hematuria, lymphadenitis, and lymphadenopathy. Cerebral edema, hemorrhage (intracranial hypertension), and mental
changes have been noted for foreign species.
Treatment consists of placing cellophane tape over the affected area, removing it, and doing this again (to take out the setae); washing the area with warm soap and water and repeating
this; and finally applying the cream previously mentioned.
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ten lasting 24 h. Localized tissue changes and necrosis have been
reported, and severe envenomations may cause nausea and vomiting, changes in heart rate, vertigo, and headache. In the most severe cases, there can be mental disturbances. Treatment is nonspecific, but washing and the application of a cream containing
hydrocortisone, diphenhydramine, and tetracaine (Itch Balm Plus,
Sawyer) is of value.
DIPLOPODA (MILLIPEDES)
These arthropods are cylindrical, wormlike creatures, mahogany to
dark brown or black in color, bearing two pairs of jointed legs per
segment and ranging in length from 20 to 300 mm. In some parts
of the world, particularly Australia and New Guinea, the repellent
secretions expelled from the sides of their bodies contain a toxin
of quinone derivatives and a variety of complex substances such
as iodine and hydrocyanic acid, which the animal makes use of to
produce hydrogen cyanide. Some species can spray these defensive secretions, and eye injuries, though rare in the United States,
are not uncommon.
The lesions produced by millipedes are generally known as
“burn” injuries and consist of a burning or prickling sensation and
development of a yellowish or brown-purple lesion; subsequently
a blister containing serosanguinous fluid forms, which may rupture. Eye contact can cause acute conjunctivitis, periorbital edema,
keratosis, and much pain; such an injury must be treated immediately. Skin treatment consists of washing, washing, and washing
the area thoroughly with soap and water and applying the cream
as previously mentioned.
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Formicidae (Ants)
INSECTA
Lepidoptera (Caterpillars, Moths,
and Butterflies)
The urticating hairs, or setae, of caterpillars are effective defensive
weapons that protect some species from predators. The setae are
attached to unicellular poison glands at the base of each hair. Both
the larvae and the adults are capable of stinging, either by direct
contact with the setae or indirectly when the creature becomes irritated. It appears that contraction of the caterpillar’s abdominal
muscles is sufficient to release the barbs from their sockets, allowing them to become airborne. Some caterpillars have a disagreeable smell or taste and are avoided by birds and other animals. The toxin found in the venom glands of some caterpillars
The stinging properties of the ants need no introduction. Most
species sink their powerful mandibles into the flesh, providing
leverage, and then drive their stings into the victim. Most ants have
stings, but those that lack them can spray a defensive secretion
from the tip of the gaster, which is often placed in the wound of
the bite. Ants of the different species vary considerably in length,
ranging from less than 1.5 mm to over 35 mm. In the United States,
the clinically important stinging ants are the harvesting ants
(Pagonomyrmex), fire ants (Solenopsis), and little fire ants (Ochetomyrmex). The harvester ants are large red, dark brown, or black
ranging in size from 6 to 10 mm and having fringes of long hairs
on the posterior of their heads. They are vicious stingers, and their
venom is said to have strong cholinergic properties.
The venoms of the ants vary considerably. The venoms of the
Ponerinae and Ecitoninae are proteinaceous in character, as is that
of the Pseudomyrmex. The Myrmecinae venoms are a mixture of
amines, enzymes and proteinaceous materials, histamine,
hyaluronidase, and phospholipase A. Formicinae ant venom contains about 60% formic acid. Fire ants are unique in that while they
are poor in polypeptides and proteins, they are rich in alkaloids,
some 95%, and these appear to be the cause of pruritic pustules
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turnal dispersal flights they are attracted to porch or artificial light.
Once there, they do not seek to escape until dawn. Indeed, at the
author’s ranch in Portal, Arizona, more than 100 reduviids have
been captured in a single night using bright artificial light. The average length of these bugs was 19 mm.
The venom of these bugs appears to have apyrase activity and
to lack 5-nucleotidase, inorganic pyrophosphatase, phosphatase,
and adenylate kinase activities, but it is fairly rich in protease properties. It inhibits collagen-induced platelet aggregation. It is said
to be a protein of 16 to 19 kDa.
The bites of Triatoma species are definitely painful and give
rise to erythema, pruritus, increased temperature in the bitten part,
localized swelling, and—in those allergic to the saliva—systemic
reactions such as nausea and vomiting and angioedema. With some
bites the wound area will slough, leaving a depression. Treatment
consists of cleansing the area and applying the cream previously
described.
The water bugs are water-dwelling true bugs of which there
are at least three families: Naucordiae, Belostomatidae, and
Notonectidae that are capable of biting and evenomating humans.
They are found in lakes, ponds, marshes, quiet fresh water, and
swimming pools. The most common biter in the United States is
Lethocerus americanus, a Belostomatidae, ranging in length from
12 to 70 mm, but some water bugs may reach 150 mm. The dorsal side is usually tan or brown, but it may be brightly colored,
while the ventral side is brown. They are very strong insects and
can immobilize snails, tadpoles, salamanders, and even small fish
and water snakes. They are sometimes known as “toe biters” or
“electric light bugs.” In some parts of the world they are eaten in
stews, but that is not likely to happen in the United States.
The venomousness of the water bugs has been attributed to
their saliva, which is said to contain digestive enzymes, neurotoxic
components, and hemolytic fractions. ApoLp-III has been isolated
from the hemolymph of Lathocerus medius. It has a M(r) of 19,000,
and an amino acid composition high in methionine. If molested,
water bugs will bite, and some species can envenomate in or out
of the water. Their bites give rise to immediate pain, some localized swelling, and—in one case seen by the author—induration
and the formation of a small papule. Treatment consists of cleansing the areas and applying the cream previously noted.
There are some arthropods that are “poisonous” as opposed
to “venomous”; that is, they have no mechanism for delivering their
toxin and the poison must come through their being crushed or
eaten. These would include, among others, the darkling beetles or
stink bugs (Eleodes), and the blister beetles (Epicauta), for which
cantharidin is known.
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and necrosis (Blum 1989). The sting of the fire ant gives rise to a
painful burning sensation, after which a wheal and localized
erythema develop, leading in a few hours to a clear vesicle. Within
12 to 24 h, the fluid becomes purulent and the lesion turns into a
pustule. It may break down or become a crust or fibrotic nodule.
In multiple stingings there may be nausea, vomiting, vertigo, increased perspiration, respiratory difficulties, cyanosis, coma, and
even death. Cross exposure to the venom of other species of ants
is possible. Treatment of ant stings is dependent upon their number, whether an allergic reaction is involved, and whether there are
possible complications.
Apidae (Bees)
In this family we include the bumble bees, honey bees, carpenter
bees, wasps, hornets, and yellow jackets. The commonest stinging
bee is Apis mellifera, but with the introduction and rapid spread of
the Africanized bee, Apis mellifer adansonii, in the United States,
the incidence of Hymenoptera poisonings is increasing. In 1996
there were at least 58 deaths and more than 1000 incidents of
Africanized bee stings in Mexico and the United States. The venom
of the Africanized bee is not remarkably different from that of the
European bee, A. m. mellifer. The former bee is smaller and gives
less venom, but its agressiveness is such that attacks of 50 to 500
bees are not unusual. The overwhelming dose of apamine, which
is thought to be lethal factor, results in the serious or even fatal
poisoning by this arthropod. In addition to apamine, the venom
contains biologically active melittin synergized by phospholipase
A2, hyaluronidase, histamine, dopamine, and a mast cell–degranulating peptide, among other components. It is said that 50 stings
can be serious and lead to respiratory dysfunction, intravascular
hemolysis, hypertension, myocardial damage, hepatic changes,
shock, and renal failure. With 100 or more stings, death can occur.
A novel Fab-based antivenom for massive bee attacks has been reported but has not undergone clinical trial at the time of this writing. It could be of value in those cases where the patient survives
the initial onslaught of the poisoning and before serious sequelae
develop.
Heteroptera (True Bugs)
The clinically most important of the true bugs are the Reduviidae
(the reduviids): the kissing bug, assassin bug, wheel bug, or conenose bug of the genus Triatoma. Generally, they are parasites of
rodents and common in the nests of wood rat or in wood piles.
These are elongated bugs with freely movable, cone-shaped heads
and straight beaks. The most commonly involved species appear
to be Triatoma protracta, T. rubida, T. magista, Reduvius personatus, and Arilus cristatus. Most are good fliers. During their noc-
REPTILES
Lizards
The Gila monster (Heloderma suspectum) and the beaded lizards
(Heloderma horridum) are divided into five subspecies. These
large, corpulent, relatively slow-moving, and largely nocturnal reptiles have few enemies other than humans. They are far less dangerous than is generally believed. Their venom is transferred from
venom glands in the lower jaw through ducts that discharge their
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CHAPTER 26 TOXIC EFFECTS OF TERRESTRIAL ANIMAL VENOMS AND POISONS
Snakes
many other islands. Some medically important venomous snakes
and their general distribution are shown in Table 26-3.
Snake Venoms The venoms of snakes are complex mixtures,
chiefly proteins, a number of which have enzymatic activities. In
some species the most active component of the venom is a peptide
or polypeptide. Proteins and peptides make up about 90 to 95 percent of the dry weight of the venom. In addition, snake venoms
contain inorganic cations such as sodium, calcium, potassium, magnesium, and small amounts of metals: zinc, iron, cobalt, manganese, and nickel. The importance of the metals in snake venoms
is not clear, although in the case of some elapid venoms zinc
ions appear to be necessary for anticholinesterase activity, and it
has been suggested that calcium may play a role in the activation
of phospholipase A and the direct lytic factor. Some proteases appear to be metalloproteins. Some snake venoms also contain carbohydrates (glycoproteins), lipids, and biogenic amines, whereas
others contain free amino acid (Russell, 1967, 1980b, 1983; Tu,
1977; Elliott, 1978; Lee, 1979; Habermehl, 1981). A recent contribution on snake toxins, using mass spectrometric immunoassay
and bioactive probe techniques, has been published by Tubbs et al.
(2000).
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contents near the base of the larger teeth of the lower jaw. The
venom is then drawn up along grooves in the teeth by capillary action. The venom of this lizard has serotonin, amine oxidase, phospholipase A, and proteolytic as well as hyaluronidase activities but
lacks phosphomonoesterase and phosphodiesterase, acetylcholinesterase, nucleotidase, ATP-ase, deoxyribonuclease, ribonuclease, amino acid oxidase, and fibrinogenocoagulase activities.
The high hyaluronidase content seems to be consistent with the tissue edema seen in many clinical cases, and the low proteolytic activity is also consistent with the minimal tissue breakdown seen in
clinical cases. The injection of large doses of Heloderma venom
produces a fall in systemic arterial pressure with a decrease in circulating blood volume, tachycardia, and respiratory distress; in
lethal doses, there is a loss of ventricular contractility (Russell and
Bogert, 1981). An excellent review on the biology of the Gila monster has been published by Brown and Carmony (1991).
More recently the venom has been shown to contain a 25,376kDa protein, helothermine, containing 223 amino acids and four
pairs of disulfide bonds. Its mode of action appears to involve Ca2
inhibitor from the sarcoplasmic reticulum (Morrissette et al., 1995).
Its action on cerebellar granule cells has been described (Nobile et
al., 1996). A fraction causing hemorrhage in internal organs and
the eye, a glycoprotein of 210 amino acid residues with plasma
kallikrein-like properties, has also been described (Dalla and Tu,
1997). According to Horikawa et al. (1998), a 35 – amino acid
residue, helodermin, that produces hypotension is partially attributed to activation of glibenclamide-sensitive K channels. Other
definitive works on Heloderma venom have been published by
Uddman et al. (1999) and Pohl and Wañk (1998). Treatment of
Heloderma bites tends to be empiric. An experimental antivenom
was once produced at the University of Southern California, but as
an IgG product it elicited a large number of sensitivity reactions
and its production was halted.
From the beginnings of the human record, few subjects have stimulated minds and imaginations more than the study of snakes and
snake venoms. No animal has been more worshiped yet more cast
out, more loved yet more despised, more collected yet more trampled on than the snake. The essence of the fascination for and fear
of snakes lies in their venom. In times past, the consequences of
bites by venomous snakes often were attributed to forces beyond
nature, sometimes to vengeful deities that were thought to be embodied in the serpents. To early peoples, the effects of snakebite
were so surprising and violent that snakes and their poisons were
shrouded with myth and superstition.
Among the more than 3500 species of snakes, approximately
400 are considered sufficiently venomous to be dangerous to humans (Dowling et al., 1968; Minton and Minton, 1969; Harding
and Welch, 1980; Russell, 1980b, 1983; Junghanss and Budio,
1996). Venomous species can be divided into the Elapidae—the
cobras, kraits, mambas, and coral snakes; the Hydrophiidae—the
true sea snakes; the Laticaudidae—the sea kraits; the Viperidae—
the Old World vipers and adders and the New World Crotalidae
(now a subfamily), the rattlesnakes, water moccasins, copperheads,
fer-de-lances, and bushmasters and some Asian species; and certain Colubridae, of which clinically the most important are the
boomslang and bird snake of Africa and the rednecked keelback
of Asia. However, several other colubrids must be viewed with concern (Minton and Minton, 1969; Minton, 1976: Mebs, 1977). There
are no poisonous snakes in New Zealand, Hawaii, Ireland, and
955
Enzymes The venoms of snakes contain at least 25 enzymes, although no single snake venom contains all of them. Enzymes are
the proteins responsible for the catalysis of many specific biochemical reactions that occur in living matter. They are the agents
on which cellular metabolism depends. Enzymes are universally
accepted as proteins, although a few have crucial dependencies on
certain nonprotein prosthetic groups, or cofactors. All living cells
contain enzymes. Some of the more important snake venom enzymes are shown in Table 26-4.
Proteolytic enzymes catalyze the breakdown of tissue proteins
and peptides. They are known as proteolytic enzymes, peptide hydrolases, proteases, endopeptidases, peptidases, and proteinases.
There may be several proteolytic enzymes in a single venom. The
proteolytic enzymes have molecular weights between 20,000 and
95,000. Some are inactivated by edetic acid (EDTA) and certain
reducing agents. The role of metal ions in catalysis was demonstrated many years ago by Wagner and Prescott (1966). Metals appear to be intrinsically involved in the activity of certain venom
proteases and phospholipases.
The crotalid venoms examined so far appear to be rich in proteolytic enzyme activity. Viperid venoms have lesser amounts,
whereas elapid and sea snake venoms have no proteolytic activity
or very little. Venoms that are rich in proteinase activity are associated with marked tissue destruction.
Arginine ester hydrolase is one of a number of noncholinesterases found in snake venoms. The substrate specificities
are directed to the hydrolysis of the ester or peptide linkage, to
which an argine residue contributes the carboxyl group. This activity is found in many crotalid and viperid venoms and some sea
snake venoms but is lacking in elapid venoms with the possible
exception of Ophiophagus hannah. It was first demonstrated by
Deutsch and Diniz (1955) in 15 snake venoms and subsequently
has been identified in many others. Some crotalid venoms contain
at least three chromatographically separable arginine ester hydrolases. The bradykinin-releasing and perhaps bradykinin-clotting
activities of some crotalid venoms may be related to esterase
activity.
Thrombin-like enzymes are found in significant amounts in
the venoms of the Crotalidae and Viperidae, whereas those of
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Table 26-3
Some Medically Important Snakes of the World
SCIENTIFIC AND COMMON NAMES
Crotalids
Agkistrodon bilineatus—cantil
Agkistrodon contortrix—copperhead
Mexico south to Guatemala and Nicaragua
New York south to Florida and west to Nebraska
and Texas
Caspian Sea to Japan
New York to Missouri
Much of southeast Asia
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Agkistrodon halys—mamushi
Agkistrodon piscivorus—eastern cottonmouth
Calloselasma (Agkistrodon) rhodostoma—Malayan
pit viper
Bothrops asper and/or atrox—fer-de-lance
—barba amarillia
—terciopelo
Bothrops jararaca—jararaca
Bothrops jararacussu—jararacussu
Bothrops neuwiedi—jararaca pintada
Crotalus adamanteus—eastern diamondback rattlesnake
Crotalus atrox—western diamondback rattlesnake
Crotalus basiliscus—Mexican west-coast rattlesnake
Crotalus scutulatus—Mojave rattlesnake
Crotalus viridis helleri—southern Pacific rattlesnake
Trimeresurus flavoviridis—habu
Trimeresurus mucrosquamatus—Chinese habu
DISTRIBUTION
Viperids
Bitis arietans—puff adder
Bitis caudalis—horned adder
Causus sp.—night adders
Cerastes cerastes—horned viper
Cerastes vipera—Sahara sand viper
Daboi (Vipera) russelli
Echis carinatus—saw-scaled viper
Echis coloratus—saw-scaled viper
Vipera ammodytes—long-nosed viper
Vipera berus—European viper
Vipera lebetina—Levantine viper
Vipera xanthina—Near East viper
Elapids
Coral snakes (c.s.)
Calliophis species—Oriental c.s.
Micrurus alleni—Allen’s c.s.
Micrurus corallinus—c.s.
Micrurus frontalis—southern c.s.
Micrurus fulvius—eastern c.s.
Micrurus mipartitus—black-ringed c.s.
Micrurus nigrocinctus—black-banded c.s.
Cobras
Hemachatus haemachatus—Ringhals cobra
Southern Sonora to Peru and northern Brazil
Brazil, Paraguay, and Argentina
Brazil, Bolivia, Paraguay, and Argentina
Brazil, Bolivia, Paraguay, northern Argentina
Southeastern United States
Southwestern United States to central Mexico
Oaxaca and west coast of Mexico
Central California to New Mexico
West Coast, southern California
Amami and Okinawa islands
Taiwan and southern China west through Vietnam
and Loas to India
Morocco and western Arabia through much
of Africa
Angola south through Nambia into central
and part of south Africa
Most of Africa south of the Sahara
Sahara, Arabian peninsula to Lebanon
Central Sahara to Lebanon
Indian subcontinent, southeast China to Taiwan and
parts of Indonesia
Southern India to northern and tropical Africa
Eastern Egypt, western Arabian peninsula north
to Israel
Italy through southeast Europe, Turkey, Jordan to
northwest Iran
British Isles through Europe, to northern Asia
Cyprus through Middle East to Kashmir
European Turkey and Asia Minor
Southeast Asia, Orient
Atlantic Nicaragua to Panama
Southern Brazil to Uruguay, northern Argentina
Southwestern Brazil, northern Argentina, Uruguay,
Paraguay, and Bolivia
Southeastern, southern United States and north
central Mexico
Venezuela and Peru to Nicaragua
Southern Mexico to northwest Colombia
Southeastern and southern Africa
(continued)
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Table 26-3
Some Medically Important Snakes of the World (continued)
SCIENTIFIC AND COMMON NAMES
DISTRIBUTION
Africa and part of Arabian peninsula
Thailand and South China to Taiwan
Most of Indian subcontinent
West Africa and southern Egypt to near the Cape
Northern Pakistan to Iran, southern Russia
Philippines
Malayan peninsula and Indonesia
Nambia, Botswana south to the Cape
Indian subcontinent, China and Philippines
Egypt to Iran
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Naja haje—Egyptian or brown cobra
Naja atra—Chinese cobra
Naja naja—Indian cobra
Naja nigricollis—spitting cobra
Naja oxiana—Central Asian cobra
Naja philippinensis—Philippine cobra
Naja sputatrix—Malayan cobra
Naja nivea—Cape or yellow cobra
Ophiophagus hannah—king cobra
Walterinnesia aegyptia—desert blacksnake or desert
cobra
Kraits and mambas
Bungarus caeruleus—Indian or blue krait
Bungarus candidus—Malayan krait
Bungarus multicinctus—many-banded krait
Dendroaspis polylepis—black mamba
India, Pakistan, Sri Lanka, Bangladesh
Thailand, Malaysia, Indonesia
Southern China to Hainan, Taiwan
Ethiopia and Somalia to Angola, Zambia, Nambia,
southwest Africa
Australian elapids
Acanthophis antarcticus—common death adder
Notechis scutatus—tiger snake
Oxyuranus scutellatus—Taipan
Pseudechis australis—mulga
Most of Australia, Moluccas, New Guinea
Southeastern Australia
Northern coastal Australia, parts of New Guinea
Most of Australia except southeast and southern coast,
New Guinea
Most of Australia except east and southeast coast
Eastern Australia
Pseudonaja nuchalis—western brown snake
Pseudonaja textilis—eastern brown snake
NOTE:
957
The common names in this table are those generally employed as literature identifications for the snakes. However, these names may not be the ones used by people in
the specific area where the snake abounds.
Elapidae and Hydrophiidae contain little or none. The mechanism
of fibrinogen clot formation by snake venom thrombin-like
enzymes invokes the preferential release of fibrinopeptide A (or
B); thrombin releases fibrinopeptides A and B. Paradoxically, the
thrombin-like enzymes have been shown to act as defibrinating anticoagulants in vivo, whereas in vitro they clot plasma, citrated or
heparinized plasma, or purified fibrinogen. Because of the obvious
clinical potential of these enzymes as defibrinating agents, more
attention has been directed toward the characterization and study
of the thrombin-like enzymes than toward those of the other venom
procoagulant or anticoagulant enzymes. The proteolytic action of
thrombin and thrombin-like snake venom enzymes is shown in
Table 26-5. This table also shows comparisons of ancrod (from
Calloselasma rhodostoma), batroxobin (from Bothrops moojeni),
crotalase (from Crotalus adamanteus), gabonase (from Bitis
gabonica), and venzyme (from Agkistrodon contortrix); while
Table 26-6 shows the molecular size of some thrombin-like
enzymes.
Thrombin-like enzymes have been purified from the venoms
of Crotalus adamanteus (crotalase) Crotalus horridus horridus,
Calloselasma (Agkistrodon) rhodostoma (ancrod), Agkistrodon
contortrix contortrix, Deinagkistrodon (Agkistrodon) acutus, Bothrops atrox (batroxobin), Bothrops marajoensis, Bothrops moojeni,
Trimeresurus gramineus, Trimeresurus okinavensis, and Bitis
gabonica. All these enzymes appear to be glycoproteins; with the
exception of two, they appear to have molecular weights in the
range of 29,000 to 35,000.
Thrombin-like enzymes have been used clinically and in animals for therapeutic and investigative studies. In experimentally
induced venous thrombosis in dogs, treatment with ancrod before
the formation of the thrombus prevented thrombosis and ensured
vessel patency. However, ancrod had no thrombolytic effect when
administered after thrombus formation. Trials of ancrod versus heparin and ancrod versus streptokinase in the treatment of deep venous thromboses of the lower leg have been conducted. Crotalase
has been employed to evaluate the role of fibrin deposition in burns
in animals (Bajwa and Markland, 1976). The role of fibrin deposition has been evaluated in tumor metastasis, in which fibrinogen
is removed by treatment with ancrod or batroxobin. Ancrod also
Table 26-4
Enzymes of Snake Venoms
Proteolytic enzymes
Arginine ester hydrolase
Thrombinlike enzyme
Collagenase
Hyaluronidase
Phospholipase A2(A)
Phospholipase B
Phospholipase C
Lactate dehydrogenase
SOURCE:
Copyright © 2001 by The McGraw-Hill Companies
Russell, 1983, with permission.
Retrieved from: www.knovel.com
Phosphomonoesterase
Phosphodiesterase
Acetylcholinesterase
RNase
DNase
5-Nucleotidase
NAD-nucleotidase
L-Amino acid oxidase
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Table 26-5
Proteolytic Action of Thrombin and Thrombin-like Snake Venom Enzymes
Action on Human Fibrinogen
ENZYME
PROTHROMBIN
PLATELET
ACTIVATION
CHAIN
OF
FRAGMENT
AGGREGATION
OF
OF
RELEASED
DEGRADATION
FACTOR XIII
CLEAVAGE
AND RELEASE
FACTOR VIII
FACTOR V
AB
(A)
Yes
Yes
Yes
Yes
Yes
A*
(A)† or (B)‡
No
Yes or no§
No
No
No
B
n.d.#
Incomplete
n.d.
No
n.d.
n.d.
AB
n.d.
Yes
n.d.
n.d.
n.d.
n.d.
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Thrombin
Thrombinlike
enzymes
Agkistrodon
c. contortrix
venom
Bitis gabonica
venom
ACTIVATION
FIBRINOPEPTIDES
ACTIVATION
*Includes ancrod, batroxobin, crotalase, and the enzyme from T. okinavensis.
†Ancrod [batroxobin degrades (A) chain of bovine but not human fibrinogen].
‡Crotalase.
§Fragment I released by crotalase and Agkistrodon contortrix venom but not by ancrod or batroxobin.
#n.d. not determined.
SOURCE: Russell, 1983, with permission.
EDTA inhibits the collagenolytic effect but not the argine esterase
effect.
Hyaluronidase catalyzes the cleavage of internal glycoside
bonds in certain acid mucopolysaccharides. This results in a decrease in the viscosity of connective tissues. The breakdown in the
hyaluronic barrier allows other fractions of venom to penetrate the
tissues. The enzyme is thought to be related to the extent of edema
produced by the whole venom, but the degree to which it contributes to clinical swelling and edema is not known. The enzyme
also has been referred to as the “spreading factor.”
Phospholipase enzymes are widely distributed throughout the
tissues of animals, plants, and bacteria. Some venoms are the
richest sources of phospholipase A2 (PLA2) enzymes. PLA2
catalyzes the Ca2-dependent hydrolysis of the 2-acyl ester bond,
producing free fatty acids and lysophospholipid. Many PLA2s have
been sequenced. They have approximately 120 amino acids and 14
has been used to prevent the deposition of fibrin on prosthetic heart
valves implanted in calves (Russell, 1980b, 1983). Ancrod and
batroxobin have been used as defibrinogenating agents in clinical
conditions of deep venous thrombosis, myocardial infarction, pulmonary embolus, central retinal vein occlusion, peripheral vascular disease, stroke, angina, glomerulonephritis, and renal transplant
rejection (Markland, 1998).
Considerable study has been given to the hemostatic
properties of venoms (Meier and Stocker, 1991; Ouayang and
Huang, 1992; Hutton and Warrell, 1993; Marsh, 1994; Markland,
1998). The hemostatically active components are summarized in
Table 26-7.
Collagenase is a specific kind of proteinase that digests collagen. This activity has been demonstrated in the venoms of a number of species of crotalids and viperids. The venom of Crotalus
atrox digests mesenteric collagen fibers but not other protein.
Table 26-6
Comparison of Snake Venom Thrombin-like Enzymes
CARBOHYDRATE
MOLECULAR
CONTENT
NH2-TERMINAL
ACTIVE SITE
ACTIVE SITE
VENOM ENZYME
WEIGHT
%
RESIDUE
SERINE
HISTIDINE
Calloselasma rhodostoma
Crotalus adamantus
Bothrops marajoensis
Bothrops moojeni
Crotalus horridus horridus
Deinagkistrodon acutus
Trimeresurus gramineus
Trimeresurus okinavensis
Agkistrodon contortrix contortrix
Bitis gabonica
59,000
32,700
31,400
36,000
19,400
33,500
27,000
34,000
100,000
32,500
36.0
8.3
High
5.8
Very low
13.0
25.0
6.0
n.d.
n.d.
Val
Val
Val
Val
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.*
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
*n.d. not determined.
SOURCE: Russell, 1983 revised, with permission.
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959
Table 26-7
Snake Venom Proteins Active on the Hemostatic System
GENERAL FUNCTIONAL ACTIVITY
Factor V activating
Factor X activating
Factor IX activating
Prothrombin activating
Fibrinogen clotting
Protein C activating
Factor IX/factor X-binding protein
Thrombin inhibitor
Phospholipase A
Fibrin(ogen) degradation
Plasminogen activation
Hemorrhagic
Platelet aggregation inducers
Inhibitors of platelet aggregation
Inhibitors of SERPINS
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Procoagulant
SPECIFIC BIOLOGICAL ACTIVITY
Anticoagulant
Fibrinolytic
Vessel wall interactive
Platelet active
Plasma protein inactivators
SOURCE:
From Markland, 1998, with permission.
Cys residues forming seven disulfide bonds. The enzymes are
widely distributed in the venoms of elapids, vipers, crotalids, atractaspids, sea snakes, and several colubrids so far studied. Although
the sequences of these enzymes are homologous and their enzymatic active sites are identical, they differ widely in their pharmacologic properties. For example, taipoxin, a PLA2 enzyme from
the venom of the Australian elapid Oxyuranus scutellatus, has an
intravenous LD50 in mice of 2 g/kg, whereas the neutral PLA2
from Naja nigricollis has an LD50 of 10,200 g/kg, even though
N. nigricollis PLA2 is enzymatically more active.
Recent studies have shown that PLA2 enzymes can exert their
pharmacologic effects by different mechanisms: hydrolysis of
membrane phospholipids, liberation of pharmacologically active
products, and effects independent of enzymatic action. Similarly,
snake venom PLA2 enzymes can be separated into three major
groupings depending on their pharmacologic activities: lowtoxicity enzymes (LD50 1 mg/kg), high-toxicity enzymes
(1 mg/kg LD50 0.1 mg/kg), and presynaptically acting toxins
(LD50 0.1 mg/kg). Interested readers are referred to reviews by
Rosenberg (1978, 1979, 1990).
Phosphomonoesterase (phosphatase) is widely distributed in
the venoms of all families of snakes except the colubrids. It has
the properties of an orthophosphoric monoester phosphohydrolase.
There are two nonspecific phosphomonoesterases, and they have
optimal pH at 5.0 and 8.5. Many venoms contain both acid and alkaline phosphatases, whereas others contain one or the other.
Phosphodiesterase has been found in the venoms of all families of poisonous snakes. It is an orthophosphoric diester phosphohydrolase that releases 5-mononucleotide from the polynucleotide chain and thus acts as an exonucleotidase, attacking DNA
and RNA. More recently, it has been found that it also attacks derivatives of arabinose.
Acetylcholinesterase was first demonstrated in cobra venom
and is widely distributed throughout the elapid venoms. It is also
found in sea snake venoms but is totally lacking in viperid and crotalid venoms. It catalyzes the hydrolysis of acetylcholine to choline
and acetic acid. The role of the enzyme in snake venoms is not
clear.
RNase is present in some snake venoms in small amounts as
the endopolynucleotidase RNase. It appears to have specificity toward pyrimidine-containing pyrimidyladenyl bonds in DNA. The
optimum pH is 7 to 9 when ribosomal RNA is used as the substrate. This enzyme in Naja oxiana venom has a molecular weight
of 15,900.
DNase acts on DNA and gives predominantly tri- or higher
oligonucleotides that terminate in 3 monoesterified phosphate.
Crotalus adamanteus venom contains two DNases, with optimum
pH at 5 and 9.
5-Nucleotidase is a common constituent of all snake venoms;
in most instances it is the most active phosphatase in snake venoms. It specifically hydrolyzes phosphate monoesters, which link
with a 5 position of DNA and RNA. It is found in greater amounts
in crotalid and viperid venoms than in elapid venoms. The molecular weight as determined from amino acid composition and gel
filtration with Naja naja atra venom has been estimated at 10,000.
The enzyme from N. naja venom is enhanced by Mg2, is inhibited by Zn2, is inactivated at 75°C at pH 7.0 or 8.4, and has an
isoelectric point of about 8.6. That from Agkistrodon halys
blomhoffi shows a pH optimum of 6.8 to 6.9, with activity being
enhanced by Mg2 and Mn2 and inhibited by Zn2. The enzyme
has a low order of lethality, and its pharmacologic role in the venom
is not understood (Russell, 1980b, 1983).
Nicotinamide adenine dinucleotide (NAD) nucleotidase has
been found in a number of snake venoms. This enzymes catalyzes
the hydrolysis of the nicotinamide N-ribosidic linkage of NAD,
yielding nicotinamide and adenosine diphosphate riboside. Its optimum pH is 6.5 to 8.5; it is heat-labile, losing activity at 60°C. Its
toxicologic contribution to snake venoms is not understood.
L-Amino acid oxidase has been found in all snake venoms
examined so far. It gives a yellow color to the venom. This enzyme
catalyzes the oxidation of L--amino and -hydroxy acids. This
activity results from a group of homologous enzymes with molecular weights ranging from 85,000 to 150,000. It has a high content
of acidic amino acids. We found that the mouse intravenous LD50
of the enzyme from Crotalus adamanteus venom was 9.13 mg/kg
body weight, approximately 4 times less than the lethal value of
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the crude venom, and that this enzyme had no effect on nerve, muscle, or neuromuscular transmission (Russell, 1980b, 1983).
Lactate dehydrogenase catalyzes the equilibrium between lactic acid and pyruvic acid. It is found in almost all animal tissues.
It is a tetamer of 140,000 kDa and consists of two subunits of about
35,000 kDa.
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Polypeptides Snake venom polypeptides are low-molecularweight proteins that do not have enzymatic activity. During the past
30 years, a number of peptides of snake venoms have been characterized. In 1965, the first paper on the amino acid composition
of a snake venom peptide was published (Yang, 1965), and at the
First International Symposium on Animal Toxins in 1966, Tamiya
presented a paper on the chromatography, crystallization, electrophoresis, ultracentrifugation, and amino acid composition of the
venom of the sea snake Laticauda semifasciata. Most of the lethal
activity of the poison was recovered as two toxins, erabutoxin a
and b, using carboxymethylcellulose chromatography; 30 percent
of the proteins were erabutoxins. The homogeneity of the crystalline toxins was demonstrated by rechromatography, disk electrophoresis, and ultracentrifugation (Tamiya et al., 1967). At the
same meeting, Su and colleagues (1967) reported the isolation of
a cobra “neurotoxin.” The toxin was separated by repeated fractionation with ammonium sulfate. Since 1966, more than 80
polypeptides with pharmacologic activity have been isolated from
snake venoms. Interested readers will find definitive reviews on
these peptides in the works of Tu (1977), Elliott (1978), Rosenberg
(1978), Lee (1979), Eaker and Wadstrom (1980), and Gopalakrishnakone and Tan (1992). More recently, erabutoxin a (Ea), a
short-chain curamimetic, has been crystallized in monomeric and
dimeric forms (Nastopoulos et al., 1998). Erabutoxin b (Eb) is said
to be relatively ineffective at the mammalian neuromuscular junction (Vincent et al., 1998). Another curamimetic, a long-chain
polypeptide, is alpha-cobratoxin, while a novel “neurotoxin” from
N. naja atra, having 61 amino acid residues and 8 cystine residues,
has been isolated by Chang et al. (1997).
In 1938, Slotta and Fraenkel-Conrat isolated a crystalline protein from the venom of the tropical rattlesnake Crotalus durissus
terrificus. The protein exhibited most of the toxic properties of the
crude venom and was named crotoxin. In addition to the toxic
nonenzymatic protein portion, it was found to contain the enzymes
hyaluronidase and phospholipase and possibly several others. It did
not appear to have proteolytic or coagulant properties or
5-nucleotidase activity, but it had neurotoxic, indirect hemolytic,
and smooth muscle–stimulating properties. After removal of phospholipase A, crotoxin was further separated into a general toxic
principle known as crotactin, which was found to have a greater
lethal index than that of crotoxin, and a second component that
may have been crotamine. The word crotoxin has been retained in
one form or another in the literature as an identification for 17 different separations of the venom of C. durissus terrificus over the
past 50 years. This has resulted in considerable confusion and disputes on research techniques, which could be more easily resolved
on the basis of a frank statement about the method of isolation. For
a thorough review of crotoxin, see Haberman and Breithaupt
(1978).
At present, crotoxin is considered a neurotoxic and cytolytic
PLA2 of 30 kDa consisting of two dissimilar subunits: (1) an acidic,
nontoxic component (crotapotin) without enzymatic activity and
(2) a basic, weakly toxic PLA2 component. Crotoxin accounts for
about 50 percent of the total protein of the venom. The full activity of the complex requires the two components. The principal pharmacologic property appears to be the presynaptic interference with
acetycholine release, and secondarily the densensitization of the
acelycholine receptor (Haberman and Briethaupt, 1978, Bon et al.,
1989, Fortes-Dias et al., 1999). A rabbit-raised antivenom neutralizes the lethal properties of the venom more than an equine preparation (Oshima-Franco et al., 1999). Mojave toxin, from the venom
of the rattlesnake Crotalus scutulatus scutulatus, is similar to crotoxin. It contains 123 amino acid residues and has an estimated
molecular weight of 14 kDa.
Toxicology It is not within the scope of this chapter to discuss
all the pharmacologic activities of snake venoms. Interested readers are referred to Russell (1967, 1983), Mebs (1978), to the journal Toxicon, and to articles, in the compendia of the International
Society on Toxinology for a more thorough consideration of the
specific toxicologic effects of these poisons and their components.
Since these earlier studies, more than 520 papers have been published on the toxinologic and biochemical properties of snake
venoms. Some remarks, however, may be made about the venoms
of the North American crotalids, particularly the rattlesnakes. The
LD50s of some North American snake venoms are shown in
Table 26-8.
In general, the venoms of rattlesnakes and other New World
crotalids produce alterations in the resistances (and often the integrity) of blood vessels, changes in blood cells and blood coagulation mechanisms, direct or indirect changes in cardiac and pul-
Table 26-8
LD50 by Different Routes of Injection
VENOM
INTRAVENOUS
Crotalus viridis helleri
Crotalus adamanteus
Crotalus atrox
Crotalus scutulatus
Agkistrodon piscivorus
Agkistrodon contortrix
Sistrurus miliarius
1.29
1.68
2.18
0.21
4.17
10.92
2.91
INTRAPERITONEAL
1.60
1.90
3.71
0.23
5.10
10.50
6.89
SUBCUTANEOUS
3.65
13.73
17.75
0.31
25.10
26.10
25.10
NOTE:
All determinations were made in 20-g female mice of the same group. All mice were injected within a 1-h period and
were observed for 48 h.
SOURCE: Russell, 1983, with permission.
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omous snake ends in an envenomation. Venom may not be injected.
In almost 1000 cases of crotalid bites, 24 percent did not end in a
poisoning. The incidence with the bites of cobras and perhaps other
elapids is probably higher. In the United States, 14 percent of crotalid bites are so trivial that antivenom is not recommended. It
would be difficult to detail specific treatments for the almost 400
snakes implicated in snake venom poisoning. Perhaps several recent works will suffice. For the United States, Russell (1980, 1983,
1996, 1998), Dart and Russell (1992), and Heard et al. (1999); for
Europe, Persson and Karlson-Stiber (1996) and Sorkine et al.
(1996); for Africa, Visser and Chapman (1978) and Chippaux
et al. (1996); for Central America, Russell (1997); for Australia,
Sutherland (1983) and White (1996); for the carpet viper, Warrell
and Arnett (1976); for Russell’s viper, Warrell (1989); and in general (worldwide), Dowling et al. (1968), Russell (1983), Warrell
(1996), and Junghanss and Bodio (1996).
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monary dynamics, and—with crotalids like C. durrissus terrificus
and C. scutulatus—serious alterations in the nervous system and
changes in respiration. In humans, the course of the poisoning is
determined by the kind and amount of venom injected; the site
where it is deposited; the general health, size, and age of the patient; the kind of treatment; and those pharmacodynamic principles noted earlier in this chapter. Clinical experience indicates that
death in humans may occur within less than 1 h or after several
days, with most deaths occurring between 18 and 32 h. Hypotension or shock is the major therapeutic problem in North American
crotalid bites. In some cases the hypotension is associated with
acute blood loss secondary to bleeding and/or hemolysis, but in
most patients shock is associated with a decrease in circulating
fluid volume, with varying degrees of blood cell loss. It is not surprising, therefore, to find that numerous studies have been directed
at determining the mechanisms responsible for snake venom poisoning, hypotension, and shock. These studies have been reviewed
elsewhere (Russell, 1983).
Experimentally, it has been found that an intravenous bolus
injection of a Crotalus venom causes an immediate fall in blood
pressure and varying degrees of shock, associated with initial
hemoconcentration followed by a decrease in hematocrit values.
There is increased blood volume in the lungs, an increase in pulmonary artery pressure with a concomitant decrease in pulmonary
artery flow, and a relatively stable heart stroke volume (Russell et
al., 1962).
Carlson and colleagues (1975) observed that when Crotalus
venom is given intravenously and slowly over a 30-min period,
there is hypovolemia secondary to an increase in capillary permeability to protein and red blood cells. The laboratory findings
showed initial hemoconcentration, lactacidemia, and lipoproteinemia. In cats the same findings are seen, followed by a fall in hematocrit and in some cases hemolysis related to the dose of venom.
During this period the cat may be in shock or at a near-shock level,
depending on the amount of venom injected or perfused. Respirations become labored, and if the period is prolonged, the animal
becomes oliguric, rales develop, and the animal dies.
There appears to be no doubt that the shock or hypotension
is caused by a decrease in circulating blood volume secondary to
an increase in capillary permeability, which leads to the loss of
fluid, protein, and to some extent erythrocytes. The severity of the
hypotension is dose-related, and restoration of circulating fluid volume can be achieved with intravenous fluids. In patients with hypovolemic shock due to venom, steroids are of no value, but the
use of isoproterenol hydrochloride may be indicated. Antivenom
in itself may not reverse a deep shock state, but a combination of
parenteral fluids or plasma expanders, isoproterenol hydrochloride,
and antivenom is definitely of value. Evidence to the present time
indicates that the fraction of the venom that most probably is responsible for the circulatory failure is a peptide. The properties of
this peptide have been presented elsewhere (Russell, 1996).
Snakebite Treatment The treatment of bites by venomous
snakes is now so highly specialized that almost every envenomation requires specific recommendations. However, three general
principles for every bite should be kept in mind: (1) snake venom
poisoning is a medical emergency requiring immediate attention
and the exercise of considerable judgment; (2) the venom is a complex mixture of substances of which the proteins contribute the major deleterious properties, and the only adequate antidote is the use
of specific or polyspecific antivenom; (3) not every bite by a ven-
961
ANTIVENOM
Because of their protein composition, many toxins produce an antibody response; this response is essential in producing antisera.
An antivenom consists of venom-specific antisera or antibodies
concentrated from immune serum to the venom. Antisera contain
neutralizing antibodies: one antigen (monospecific) or several antigens (polyspecific). Animals immunized with venom develop a variety of antibodies to the many antigens in the venom. The serum
is harvested, partially or fully purified, and further processed before being administered to the patient. The antibodies bind to the
venom molecules, rendering them ineffective. Antivenoms have
been produced against most medically important snake, spider,
scorpion, and marine toxins.
Antivenoms are available in several forms: intact IgG antibodies or fragments of IgG such as F(ab)2 and Fab. They are prepared through (NH4)2SO4 or Na2SO4 precipitation, pepsin or papain digestion, and other procedures, among which the elimination
of the Fc, or complement-binding and complement-sensitizing fraction, is one of the most important. The molecular weight of the intact IgG is about 150,000, whereas that of Fab is approximately
50,000.
The molecular size of IgG prevents its renal excretion and
produces a volume of distribution much smaller than that of Fab.
The elimination half-life of IgG in the blood is approximately 50
h. Its ultimate fate is not known, but most IgG is probably taken
up by the reticuloendothelial system and degraded with the antigen attached. Fab fragments have an elimination half-life of about
17 h, and are small enough to permit renal excretion.
Since all antivenom products are produced through the immunization of animals, this increases the possiblity of hypersensitivity. Type I (immediate) hypersensitivity reactions are caused by
antigen cross-linking of endogenous IgE bound to mast cells and
basophils. Binding of antigen by a mast cell may cause the release
of histamine and other mediators, producing an anaphylactic reaction. Once initiated, anaphylaxis may continue despite discontinuation of antivenin administration. An additional concern is an
anaphylactoid reaction. This is a term for a syndrome resembling
an anaphylactic reaction; its etiology is unknown but it appears to
be associated with aggregated protein in the antiserum. Protein
aggregates may activate the complement cascade, producing an
anaphylactic-like syndrome. An important difference between anaphylactic and anaphylactoid reactions is that anaphylactoid reactions are dose-dependent and may be halted by removing the anti-
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oms were judged solely on the basis of their ability to neutralize
the lethal effect of a venom. I suggest that the best solution at this
time is just to use more antivenom. Apparently, the ability of the
antigen(s) to produce the antibody(ies) necessary to neutralize
the cytolytic effect is either too weak or too small in quantity
to stimulate the neutralization necessary to alleviate the cytolytic effects of the venom to the level of other antigen/antibody
reactions.
In the United States a new Fab antivenom, CroFab, has been
developed by Therapeutic Antibodies (now Protheric). It is an ovine
antiserum. One of its advantages over the IgG product is that the
former reaches its maximum protein level in the blood in 20 to 25
min, while the IgG product requires 40 to 50 min to reach the same
level. Experiences with the efficacy and safety of the CroFab antivenom are found in Dart et al. (1997) and Seifert et al. (1997). It
has become obvious that the use of this product may require periodic administration rather than single-bolus doses of the antivenom
(Boyer et al., 1999).
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gen. Type III hypersensitivity (serum sickness) may develop several days after antivenom administration. In these cases, antigenantibody complexes are deposited in different areas of the body,
often producing inflammatory responses in the skin, joints, kidneys, and other tissues. Fortunately, these reactions are rarely serious. The risks of anaphylaxis should always be considered when
one is deciding whether to administer antivenom.
It has been said, principally by nonclinical researchers, that
antivenoms have little effect on the local tissue changes produced
by snake venoms. Perhaps this opinion now needs to be reevaluated
on the basis of new knowledge and experience. The supposition is
based on the early clinical experience, where antivenom doses were
obviously too low to effectively neutralize all the deleterious activities of a venom. For instance, in 1950 the dose of Antivenom
[Crotalidae] Polyvalent for a minimal crotalid envenomation was
1 to 3 vials, for a moderate envenomation 3 to 5 vials, and for a
severe envenomation, 5 to 8 vials. By 1970, these doses had been
revised upward (Russell, 1980), and at the present time the average dose of this antivenom in the United States is 11.3 vials, with
the average dose at the author’s medical center being 17 and as
many as 50 vials having been given. Also, hospital time has been
reduced from 5 to 8 days to 2 to 3 days, and patients leave the hospital with little or no local tissue destruction.
It has become evident that the ability of an effective antivenom
to alleviate or neutralize the deleterious properties of a venom
should be dependent on its ability to neutralize the effects of the
whole venom, and that up until the not too distant past, antiven-
ACKNOWLEDGMENT
The author wishes to acknowledge the opinions and assistance of
Professors M. Mayersohn, A, Martin, S. Yalkowsky, L. Boyer, M.
Witt, C. Witt, R. Smith, and J. McNally of the University of Arizona and Prof F. Markland of the University of Southern California. All errors of commission and omission are those of the author.
Drawings are from Smith (1997).
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