British Journal

of Anaesthesia

1995; 74: 319-327

REVIEW ARTICLE

Animal toxins
L.

KARALLIEDDE

Throughout history, envenoming by animal toxins

has fascinated humans.
Rarely has a medical
phenomenon had so much religious association,
symbolism, anecdotal cornmunication, and provoked
so much violent professional disagreement. Animal
toxins have rnade a significant contribution to
enhancing knowledge in human physiology and
pharmacology. Information on the nature and mech
anism of action of these toxins has enabled a more
scientific approach to the treatment of their in
toxications. Early and specific therapy is frequently
required after envenoming and often includes life
support and maintenance of vital functions by
mechanical ventilation, i.v. fluid and drug therapy.
The total number of snake bites throughout the
world has been estimated at 500000 per year, with
approximately 40000 deaths [5,60,81]. The ma
iority ofthese incidents occur in Asia, South America
and Africa. Snake bite is the fifth most cornmon
cause of all deaths in Burma [6], and in Sri Lanka,
two people die each day of snake bite [21]. In the
USA, 45000 snake bites occur each year of which
7000-8000 are venomous and there are between 10
and 15 deaths [13]. In the UK several incidents of
bites inflicted by foreign venomous snakes have been
recorded [67] and although there have been 11
deaths caused by adder bites from 1876 to 1941, in
recent years there have been no deaths from snake
bites. The British Military Hospital, Dharan, Nepal,
managed 58 cases of snake bite in 1989 [35]. Eighteen
deaths attributed to snake bite were reported in
Australia from 1981 to 1991 [79]. In Sweden, 44
deaths were reported frorn snake bite from 1911 to
1978, while in Finland and Sweden there are 200
bites annually. Bee and wasp stings caused 61 deaths
in the UK during a 13-yr period ending in 1972,
while in the USA, hymenoptera stings cause 40-50
deaths annually [74]. At present, an average of five
deaths occur from bee and wasp stings in the UK
annually [61]. Scorpion stings are responsible for
1000-2000 deaths each year in Mexico, and high
mortalities are also encountered in Brazil, Israel,
Trinidad, Algeria, India [85] and Jordan [37]. A total
of 38068 cases of envenoming by scorpion stings
during 1981-1986 were treated in the city of Leon,

Mexico [20]. Spider bites are associated with a

mortality of 1-17 % in Chile, Brazil [50], the
Mediterranean region [85], Israel, North Africa and
in sorne regions in the former Soviet Unon [45].
Black widow spiders caused 63 deaths in the USA
from 1950 to 1959 while the funnel-web spider is
responsible for sorne morbidity in Australia. Tick
bites cause poisoning and sometimes death in
Australia and western North America. Puffer fish
poisoning is responsible for 250 cases of poisoning a
year in Japan with a 50-60% mortality rate,
Ciguatera is the most cornmonly reported food
borne intoxication of marine origin in the United
States, accounting for 7.4 % of all food-borne
outbreaks from 1978 to 1982 [73]. It is a public
health hazard in the Pacific and Caribbean islands.
In 1968 an outbreak of paralytic shell fish poisoning
occurred in the north east coast of England affecting
78 people [55]. Scuba diving and similar recreational
activity has been associated with poisoning caused
by marine animals, particularly in the ludian and
Pacific oceans.
Figure 1 shows the principal sites of action of the
animal toxins discussed.
Snake venoms
Of the nearly 2000 different species of snakes, only
approximately 300 are venornous. Venomous snakes
are found in the families Colubridae (boomslang,
vine snake), Elapidae (cobra, krait, mamba, taipan,
tiger snake, coral snake), Hydrophidae (sea snakes),
Viperidae (old world vipers found in Europe, Africa,
Asia but not in America or Australia, saw scaled
viper, Russell's viper, puff adder, Gaboon viper),
and Crotalidae (pit vipers, found in America, Asia
and Europe, copperhead, cotton mouth, rattle
snakes).
Snake venoms are used primarily for artack and
contain components designed to irnmobilize prey
and facilitate their digestion. Over 95 % of the dry
weight of most venoms is polypeptide which includes
enzymes, toxins and small peptides, each class being
capable of modulating the physiological response of
envenomed animals. More than 20 enzymes have
been detected in snake venom and 12 are found in
the majority of venoms. Hyaluronidase is present in
all snake venoms facilitating the distribution of other

(8r. J. Anaesth. 1995; 74: 319-327)

Key words
Toxins, animal. Pharmacology, toxins.

LAKsHMAN KARALLlEDDE, MB, BS, DA, FRCA, Queen Elizabeth

Military Hospital, Stadium Road, Woolwich, London SEIS
4QH.

320

Briiish Journal of Anaesthesia

Tetrodotoxin
Saxitoxin
Batrachotoxin
Ciguatoxi~
Il Conotoxin
Sea anemone toxins
a. Scorpion toxins
~ Scorpion toxins

Dendrotoxin (mamba)
Scorpion toxins
Mast cell degranulating
peptide (honey bee)
Apamin (honey bee)
~ Bungarotoxin

ro Conotoxin ro

Agatoxins
Funnel-web toxin
Rattlesnake venoms
j3 Bungarotoxin, notexin,
Crotoxin, taipoxin
Latrodectus (black widow
spider)

a. Bungarotoxin

Cobratoxin
Sea snake venom
a. Conotoxin
Other elapid venoms
Viper venom
Honey bee
Notexin
(myotoxin)
Scorpion toxin
Box jellyfish (blue bottles)
Portuguese man of war
Latrodectus (spider)
Latrodectus (spider)
Scorpion toxin
Sting ray
Viper venom
l.oxosceles (spider)
Scorpion toxin
Honey bee
Figure 1

Principal sites of action of animal toxins.

venom components throughout the tissues of the

prey.
Elapids account for the vast rnajoriry of deaths
worldwide, particularly as a result of toxins that act
at the neurornuscular junction. The action may be at
presynaptic, postsynaptic or at both sites. Elapid
envenoming progresses along a neurotoxic course
with occasional early numbness or weakness of the
bitten extremity. Systemic manifestations occur after
about 30 min to 1 h and include ptosis, external
ophthalrnoplegia, dysphagia, salivation followed by
general paresis and respiratory failure. There are
many different snake venom neurotoxins that act
presynaptically to inhibit
the evoked release of
acerylcholine. These presynaptically acting toxins
exhibit phospholipase Az activity [11]. All agents
that inaerivate phospholipase A2 activity also in
activate their neurotoxicity, Beta bungarotoxin
(krait), notexin (Australian tiger snake), crotoxin
(Crotalus durrissus terrificus) and taipoxin (taipan)
inhibit the release of acetylcholine frorn the terminals
of neurones and sorne cholinergic neurones of the
autonomic nervous system. It takes approximately
1.5-3 h for beta bungarotoxin to cause complete
neurornuscular block when incubated with an iso-

lated neuromuscular preparation. Block occurs more

rapidly if the nerve is repetitively stimulated during
incubation. Among the most toxic components in
elapid and Hydrophidae venoms is a neurotoxin
which binds to the nicotinic acetylcholine receptor in
the postsynaptic membranes of skeletal muscles,
thus preventing binding of acetylcholine. As this
pharmacological action is similar to that of curare,
these neurotoxins are also termed curarernimetic
neurotoxins. However, in view of the presynaptic
binding shown by curare and similar non-depolariz
ing neuromuscular blocking agents, this description
is not wholly accurate as these unique neurotoxins
act on1ypostsynaptica1ly. The amino acid sequences
of most of these neurotoxins are available [25] and
accordingly they are classified into two subgroups:
short neurotoxins with 60-62 amino acid residues;
and long neurotoxins with 70-74 residues. One
species of snake may have more than one neurotoxin
and often has both short and long chain neurotoxins.
Binding studies using radiolabelled alpha neuro
toxins revealed that the toxin binding sites over
lapped acerylcholine binding sites [93]: thus the
toxins are competitive inhibitors.
Binding of a
neurotoxin to the acetylcholine receptor does not

Animal

toxins

induce ion channel opening ; the result of binding is

flaccid paralysis [43].
Of the elapid and sea snake neurotoxins, alpha
bungarotoxin from the krait has been the most
extensively studied. Alpha bungarotoxin has been
used widely for tagging, solubilization, extracting
and purifying acetylcholine receptors from muscle
and the electric organ ofthe Torpedo eel [54]. When
purified this polypeptide, with a molecular weight of
approximately 8000, has no detectable prejunctional
effects, anticholinesterase activity or ganglion block
ing properties. The most characteristic feature of the
neuromuscular block produced by alpha bungaro
toxin in contrast with the neuromuscular block
produced by curare is the absence of tetanic fade and
the presence of marked post-tetanic facilitation. The
train-of-four fades only minimally or not at all [48].
Thus postjunctonal non-depolarizing neuromuscu
lar block is not necessarily characterized by fade.
The neuromuscular blocking action of sorne cobra
toxins (type 1 cobra NT) is reversible more easily
than that of alpha bungarotoxin.
Sea snakes are the most abundant venomous
reptiles found throughout the Indian and Pacific
oceans. AlI sea snakes are poisonous. Although sea
snake venom is extremely toxic, the amount of
venom injected per bite is smaIl. Venom components
include presynaptic and postsynaptic neurotoxins
and sorne venoms appear to inhibit the actions of
acetylcholine at autonomic ganglia. A typical mani
festation of sea snake poisoning is muscle pain. In
severe poisoning myoglobinuria is detected several
hours after the bite [83].
Notexin and a myotoxin from Enhydrina schistosa
(sea snake) induce oedema and necrosis of muscle
fibres, the fibres most affected being those rich in
mitochondria [11]. The venom of the Eastern green
mamba (Kenya, Tanzania) enhances neuromuscular
transmission in vitro and the compound dendrotoxin
has been found to be 500 times more potent than 3,4diamino pyridine at augmenting responses to indirect
stimulation [25]. Release of acetylcholine is increased
by the toxin-blocking, voltage-dependent neuronal
potassium channel, thus delaying repolarization and
increasing quantal release. Fasciculin from the same
venom inhibits acetylcholinesterase by binding to a
peripheral anionic site on the enzyme. Fasciculin and
dendrotoxin act synergisticaIly increasing acetyl
choline content at the neuromuscular junction [25].
Mambas also possess toxins that bind to muscarinic
cholinoceptors. In addition, and in common with
other elapids they have postsynaptic alpha neuro
toxins.
Venom of the burrowing asps of the genus
Atractaspis have no pre- or postsynaptic neurotoxins
and the most prominent action of the toxins,
sarafotoxins, was on the heart, causing signs of
coronary insufficiency from vasospasm [7].
Cardiotoxins which cause augmentation of myo
cardial contraction at low concentrations and systolic
arrest at high concentrations have been identified
from cobra venoms [49]. Crotamines from rattle
snake venoms have a specific and unique effect on the
sodium channel of excitable membranes [49]. Phos-

321
pholipase A2 neurotoxins (e.g. beta bungarotoxin)
have been shown tu block potassium channels while
a component from the venom of the rattlesnake
(Grotalus atrox) affects caJcium channels [33].
Haemorrhagic syrnptoms are a frequent accom
paniment of bites by vipers and of some venomous
colubrids [12,34]. Venom procoagulants actvate
prothrombin, and factors V and X. Sorne venom
components have a direct thrombin-like effect.
Rattlesnake venoms can cause defibrinogenation by
activating the endogenous fibrinolytic system.
Thrombocytopenia may occur and platelet function
may be affected. Spontaneous systemic bleeding is
caused by haemorrhagins which damage the vascular
endothelium. Massive intravascular haemolysis lead
ing to renal failure follows envenomation by Russell's
viper (India [4,53], Sri Lanka [40]), which inhabits
10 South Asian countries. In Pakistan, India, Sri
Lanka, Bangladesh, Burma and Thailand it ranks
among the most important causes of snake bite
rnortaliry. The venom procoagulants activate the
clotting system with such speed and efficiency that
McFarlane was "left feeling it was too clever to be
true " [86]. Renal failure is the most devastating
effect of Russell's viper bite in Burma and Sri Lanka.
Deposition of microthrombi in the kidney contri
butes to the acute tubular necrosis which is the
commonest cause of death [6,36]. When the patient's
blood has become defibrinated and incoagulable, the
acriviry of the haemorrhagins, which damage the
vascular endothelium, and platelet abnormalities
[30] may lead to spontaneous systemic haemorrhage.
The saw scaled or carpet viper (Echis species)
probably causes more bites and deaths than any
other venomous snake worldwide [16]. Demon
stration of non-coagulating blood is the single rnost
important diagnostic test. The simple whole blood
clotting test developed in Nigeria by Warrell and
coIleagues [personal communication, 1993] should
be repeated every 6 h after the first dose of antivenom
until clotting is re-established. The test should then
be repeated daily for 3 days to ensure coagulability.
This simple aIl or nothing whole blood clotting test
proved a reliable way of identifying patients with
systemic envenomation (those that required anti
venom) [71]. The clot quality test [66,69] is of little
use in clnical management at presento After a bite
from RusseIl's viper it was found to be insensitive to
detect evolving systemic envenoming. The Malayan
pit viper produces minimal or no haemorrhagic
symptoms in spite of the fact that the patient's blood
may be incoagulable for days. This "defibrino
genation syndrome" (hypofibrinogenaemia) without
thrombocytopenia or fibrinolysis was studied ex
tensively by Reid, Chao and Thean [70] and the use
of this purified venom fraction has been under
clnical investigation as an anticoagulant [8,
84].
The smaIl scaled snake (inland taipan, Oxyuranus
microlepidotus) found in remete areas of Westem
Queensland lays good claim to being the most
venomous snake in the world, in view of its lethal
potency. The venom contains a presynaptic neuro
toxin and a prothrombin activator [56].

322
TREATMENT

The clinical management of poisonous snake bites

continues to provoke controversy. First-aid meas
ures should be determined primarily by the time and
distance from medical facilities, the species of snake
involved and the background of the health care
individuals. In all instances the victim should be
reassured, the bitten limb immobilized and rapid
transport arranged to an institution. Idenrifying the
snake is important and the snake should be killed if
it can be done so quickly and without danger. Snake
bite victims in remote areas may find additional first
aid measures helpful. Short skin incisions, 5--6 mm
in length, through the fang punctures running
parallel to the extremiry should be made. Cruciate
incisions are not recommended as the comer s of the
flaps tend to become necrotic. Sucrion should be
applied and continued for 30-60 mino In laboratory
animals, if incision and suction are started within
2 min of envenomation, 50-90 % of the venom can
be removed [41]. However, many authorities such as
Warrell [personal communication, 1993] strongly
oppose incision and suction as these procedures
could induce the risk of persistent bleeding and
damage to vital structures.
Application of toumiquets is an area of great
controversy. A light lymphatic constriction band
proximal to the site of the bite is agreed by many. If
the offending snake has been identified as an elapid,
in particular a black mamba, taipan, cobra or krait, a
toumiquet should delay the onset of respiratory
failure until the victim reaches hospital. Tourniquets
should not be used if the venom is known to cause
tissue necrosis (78). Toumiquets applied in 94 % in
a series of 36 patients after bites by the Philippine
cobra produced a delay in the onset of respiratory
paralysis; four were asymptomatic before release of
the toumiquets and in 11 symptoms worsened
precipitously after release. Most imporrantly, four
patients developed complete respiratory paralysis,
requiring artificial ventilation on removal of the
toumiquet (90).
Toumiquets should be released only when venti
latory support is at hand. In hospital, a quick
assessment of vital function should be carried out
and monitoring of these functions initiated, Level of
consciousness, respiratory funcrion (tidal volume,
ventilatory frequency, blood-gas measurements),
heart rate, arterial pressure, blood coagulabiliry,
urine output and renal function should be monitored
closely. The extent of local swelling and limb girth
should be assessed at regular intervals. Hypo
volaemia must be corrected and when necessary
ventilatory care started. Antivenom is the only
specific remedy and practical experience in Malaya
and Australia [80] suggests that the antivenom is best
given by slow i.v. infusion over 15-30 min after
diluting with isotonic fluid. Adrenaline should be
avalable for management of an anaphylactic reaction
to the antivenom.
There has been a shift in opinon since the BNF
stated that "the bite is less dangerous than the
antiserurn" [10). Although administration of anti
venom is arare clinical situation in Europe, in the

British Journal 01 Anaesthesia

rural tropics, correct administration of antivenom is
a daily matter oflife or death [23]. Administration of
antivenom has potential complications. In several
studies the incidence of hypersensitivity reactions
was 5-33 %. The incidence of serum sickness was
36-75 % occurring from 2 to 23 days after admin
istration of antivenom [17]. It is necessary to be
aware that antivenom is potentially dangerous and
should not be administered without a definite
indication (certainty of systemic envenomation), and
should not be routine for every instance of snake
bite. Sensitivity tests are unreliable and not worth
whle, and anaphylactic reactons respond well to
adrenaline given promptly.
It is recommended that a test dose of edrophonium
be gven to patients wth neurologcal sgns who have
been birten by any species of snake, especially
cobras. Atropine sulphate 0.6 mg for adults and
50 ug kg-1 for chldren i.v. is followed by edropho
nium chloride (Tensilon) 10 mg for adults and
0.25 mg kg-1 for chldren. If improvement occurs,
patients may be given a maintenance dose of
neostigmine 0.5 mg h-1 with atropine 0.15 mg h-1
[88,92].
Advocates of antivenom record the potentially
hannful result of aggressive surgical treatment.
Many eschew antivenom and recommend excisional
therapy or excision and fasciotorny [31,38]. Thera
peutic efforts directed at the site of injury are
advocated in the belief that a localized process with
destruction of platelets and coagulation factors
occurs as fluid passes through vessels or extra
vascularly in areas of injured or necrotic tissue and
this may be a major factor in many bleeding states
[77]. In 1991 a report suggested that US pit viper
bites tend to cause more tissue necrosis and may
more often require surgcal therapy [94]. Early
limited bite excision when anatomically convenient
was recommended as 75 % of the injected venom had
been demonstrated to be removed for up to 2 h after
the bite. Surgical releasing incisions were recorn
mended for any signs of circulatory compromse in
peripheral tissues or to release envenomated mus
cular compartments.
Coagulation studies should always be carred out
before surgical intervention, and coagulabiliry
should be restored. Antivenom is the first-line
treatment ro restore blood coagulability [58). Anti
venom is effective even 2-3 days after a bite and
there is report of success 7 days after envenomation
[82]. Blood products and heparin have been proved
to be of little or no value [12,58].
Prophylactic penicillin or erythromycin should be
gven with a tetanus toxoid booster. Necrotic tissue
should be debrided surgcally at an early stage and
denuded areas should be covered by skin grafts.
Fasciotorny should not be attempted before blood
coagulability has been restored and is indicated only
if there is objectve evidence of intracompartmental
hypertension (intracompartmental pressure exceed
ing 45 mm Hg) [87].
Local reaction s minimal with krait [43,47], coral
snake and sea snake envenoming, but with cobra
bites (except the Philippine and Egyptian cobras
(91)) local necrosis is a feature. Russell's viper and

Animal

323

toxins

the tropical rattlesnake (Grotalus durissus terrificus)

produce negligible local envenoming and are im
portant exceptions to the generally useful rule that
absence of local swelling after a viper bite excludes
significant envenoming [68].
Spider venoms
Neuroactive spider toxins found so far can be
classified into three main groups. Latrodectus spider
venom, as from the black widow spider (alpha
latrotoxin), has polypeptide toxins which act on
presynaptic nerve terminals opening cationic chan
nels and causing massive release of transmitter [14]
followed by depletion of synaptic vesicles at the
neuromuscular junction [29]. Alpha latrotoxin has
been used in studies of the mechanisrns of transmitter
releas e [39].
Petrenko and colleagues reported that the alpha
latrotoxin receptor is a membrane protein and is the
only presynaptic marker for which a function has
been identified [65]. A toxin acting postsynaptically
on glutamate receptors blocking synaptic trans
mission in the squid giant synapse was identified in
1980 from the "Joro" spider (Japan, East Asia) [44].
Recently, a third group of spider neurotoxins
(agatoxins) was found in the venom from the family
Agelenidae (funnel-web spider, Australia) which
contains several substances affecting synaptic trans
mission acting primarily on calciuro channels, block
ing entry of calciuro into presynaptic terrninals and
preventing release of transmitters [3].
Spider bites cause two main clinical syndromes:
necrotic and neurotoxic. Necrotic araneism follows
Loxosceles bites (Central and South America and
USA) where burning pain at the site of the bite is
followed by tissue necrosis and formation of a black
eschar. In about 12 % there are systemic effects
including macular erythema, fever, haemoglobinu
ria, jaundice and renal failure.
Bites from black widow, red back and hour glass
spiders (Latrodectus, found in the Americas, Medi
terranean, Australia, New Zealand, South and
Eastem Africa) cause muscle spasms and respiratory
embarrassment which may require ventilatory careo
Other features include vomiting, tachycardia, ir
ritability and hypertension.
Funnel-web spiders (Atrax, found in South
Eastern Australia and Tasmania) cause a painful bite
followed by nurobness, nausea, vomiting, abdominal
colic, sweating, salivation, dyspnoea, localized or
generalized muscle fasciculations and spasms. Bites
by Phoneutria (South American "banana" spider)
are the main cause of neurotoxic araneism in Brazil
and neighbouring countries.
Splinting of the bitten limb or a tight tourniquet
may delay the spread of venom until the patient
reaches hospital. Antivenoms are available for Latro
dectus, Atrax and Loxosceles bites in many countries.
Calcium gluconate, corticosteroids and ~ blockers
have been used in the management of spider bites.
Although calciuro gluconate has usually been con
sidered first-line treatment for severe envenoming
by black widow spiders, Clark and colleagues found
it ineffective for pain relief compared with a

combination
[15].

of

LV.

opioids and benzodiazepines

Scorpion venoms
Scorpion venom are known to enhance the ex
citability ofnerve and muscle cells [2]. Sorne venorns
appear to act preferentially on muscle cells [72] while
others have effects on neurones and neurotransmitter
release. Scorpion venorns have been shown to release
acetylcholine, noradrenaline and serotonin.
The alpha scorpion toxins delay inactivation of
sodium channels and thus prolong the action po
tential. The beta scorpion toxins affect activation in
addition to slowing inactivation of sodiuro channels.
The sodium channel opens at a membrane potential
level at which the channel would be normally closed
[42].
A component of scorpion venom was also found to
facilitate and then block neuromuscular transmission
in chick biventer cervicis preparations. It was shown
to induce spontaneous contractions, partIy by re
leasing acetylcholine frorn nerve endings and partly
by increasing the sodiuro permeability of muscle
membranes [76]. The first toxin that was shown to
block voltage-dependent potassium channels was
from the venom of a Mexican scorpion. Chloride
channels are important components of receptors for
inhibitory transmitters such as GABA and glycine
and a component of scorpion venom was found to
affect chloride channel activiry.
The effect of the venom in producing a contrae
ture, an initial increase in amplitude of electrically
induced muscle contractions
and spontaneous
twitching, has been attributed
to interference
with the stabilizing function of calciuro at the
muscle membrane [2]. Increased concentrations of
calciuro lessened the effects of the venom and lower
concentrations enhanced them. The venom has also
been shown to interact with receptors of the muscle
sarcoplasmic reticulum, Scorpion bites cause intense
local pain followed by sigo of autonomic nervous
system excitation
such as dilatation
of pupils,
hypersalivation, vomiting and diarrhoea. Generally,
cholinergic features are followed by adrenergic
features. Release of catecholamines produces hy
pertension, toxic myocarditis, arrhythrnias, heart
failure and pulmonary oedema. The latter is seen
following bites in India, North Africa and the Middle
East, Scorpions found in California and New Mexico
cause rnuscle fasciculations, spasms and respiratory
paralysis.
Pain requires local infiltration or ring blocks with
local anaesthetic. Antivenom is available. Aggressive
symptornatic treatment for cardiac and neurological
syrnptoms is a necessity. In patients who develop
severe adrenergic cardiovascular features, vaso
dilators (a blockers, calcium channel blockers or
ACE inhibitors) are useful. The role of cardiac
glycosides, ~ blockers and atropine is controversial.
Warrell [personal cornrnunication, 1993] advocates
antivenorn when available but this is also a subject of
vigorous debate. Serial echocardiography has been
recornrnended in the management of children after
scorpion envenomation as myocardial toxicity is a

cornmon and serious complication [46]. Syrnpto

matic patients should be treated in an intensive care
unit and be monitored invasively [32].
Hymenoptera
hornets)
It has long
factor in the
contains too
contributor

venoms (honeybees, wasps,

been known that histamine

is a major
response to bee stings. Bee venom itself
little histamine
for this to be a major
but both phospholipase
A2 and mellitin

separately or in combination cause histamine release

from skin mast cells as a result of cytolytic effects
[52]. In addition to the cytolysis of mast cells,
another component (mast cell degranulating (MCD)
peptide) causes release of histamine from mast cells
[28]. Most deaths from Hymenoptera stings are
caused by dysfunction of the body's irnmune system
whereby the venom allergens react principally with
cell-bound specific IgE to induce massive release of
histamine, leukotrienes, prostaglandins, chemotactic
factors and a myriad of other factors [89].
The dennal, respiratory, circulatory and gastro
intestinal responses that accompany this type 1
hypersensitivity reaction occur in response to a sting
after one or a few initial sensitizing stings. The
striking feature is the rapidity of death: 58 % die in
less than 1 h and over 75 % die within 6 h [26].
This is in marked contrast with the times of death
for fatal envenoming from snakes, spiders and
scorpions. Autopsy reports of 150 sting-induced
deaths showed that 70 % were caused by airway
obstruction. Anaphylactic shock was the next most
important causative factor. Major offending species
are the honeybee, yellow jacket wasp, white faced
hornet and yellow hornet.
Phospholipase A2 is the most important allergen in
the honeybee. Mellitin, the major component of
venom, causes lysis of red cells and consequently a
pigment nephropathy which is a manifestation of
massive direct poisoning. MCD peptide causes
release of histamine from mast cell granules by
fusion of the granule membranes with the mast cell
membrane and exocytosis of the granule contents
without lysis of mast cells. Apamin was the first
neurotoxin found to block potassium channels that
are activated by increased levels of internal calcium
ions. Apamin affects such channels in nerves, muscle,
erythrocytes and glandular cells. It can gain access to
the central nervous system to produce hyperactivity
and convulsions before death [33]. MCD peptide
acts on potassium channels [33] and, together with
the neurotoxic apamin and mellitin, contributes to
intravascular haemolysis, rhabdornyolysis, epider
mal necrolysis, airway obstruction and signs of
severe histamine overdose which occur with massive
honeybee envenomation.
The incidence of hypersensitivity to stings is
considerably greater than the inciden ce of death
from such stings. Within the general population,
true systemic hypersensitivity rates are reported to
vary from 0.1 to 4.0 % [95]. In the UK, sensitization
to bee venom appears to require more stings (average
81) than sensitization to wasp venom (average four
stings) [27].

Of over 1000 deaths recorded mainly from the

United States, only 2 % occurred in children less
than 10 years of age, while 50 % occurred in
individuals older than 50 years [74]. Hay fever or
asthma does not increase predisposition to venom
hypersensitivity [74]. Skin testing with pure Hyme
noptera venoms and the RAST test for detecting
specific 19B in serum are reliable methods for
detecting type 1 hypersensitivity which together
with a history of systemic reaction to a sting are
useful indicators for prevention and prophylactic
desensitization. Adrenaline is the only known ef
fective control of irnmediate hypersensitivity reac
tions. Chlorpheniramine orally or i.v., i.v. fuids
and close monitoring of respiratory, cardiac and
renal function are important constituents of im
mediate careoThe first local treatment is the removal
of the stings left in the skin by scraping them out
with a knife blade, fingernail or forceps. Patients
with a history of severe reactions should carry "sting
kits " which contain adrenaline and antihistamine
tablets and should wear an identifying tag.
The pain caused by a sting of a vespid wasp is
caused mainly by large amounts of serotonin, wasp
kinin and protease. Mastoparan, vespid chemotactic
peptides and mandarotoxin are structurally different
from apamin, mellitin and MCD peptide. However,
their sites and modes of actions are similar [59].
Sea snail: cone shells
The genus Conus ineludes several marine snails with
beautifully cone-shaped shells. These snails found in
the Pacific and Indian oceans produce an extra
ordinary variety of neurotoxins (alpha, mu and
omega conotoxins) that are deadly to their prey and
can cause fatal respiratory paralysis in humans [1].
Alpha conotoxins are potent antagonists at the
postsynaptic nicotinic receptor while the other
components act on sodium and calcium channels
[62,63]. mu Conotoxins differ from tetrodotoxin
and saxitoxin as they primarily block sodium chan
neIs in skeletal musele with less effect on action
potential conduction in motor nerves [33]. There is
no specific remedy. Cardiorespiratory resuscitation
and maintenance of vital function can be life saving.
Coral and other coelenterates
The gorgonian coral Lophogorgia rigida is a beautiful
purple fan-shaped animal that anchors itself to the
sea bottom and produces a deadly venorn, lopho
toxin, which acts on the postsynaptic nicotinic
receptor [18].
Box jelly fish (blue bottles found in Australia
and South East Asia), man of war (USA) and
sea anemones (China)
These animals discharge stinging capsules, nernato
cytes, which penetrate the skin and inject a venom
which may cause cardiorespiratory failure.
Sea
anemone toxin prolongs nerve action potential and
causes spontaneous and repetitive activiry in axons
[33]. Antivenom for one species of box jelly fish is

Animal

325

toxins

produced in Australia. These venoms produce severe

local reactions [87].
Puffer fish (japan), ciguatera (tropical and
subtropical regions) and paralytic shellfish
poisoning (PSP) (Pacific and Atlantic coasts
of North America, Japan and the western
coast of Europe and South Mrica)
Tbese unrelated groups of animals are a source of
one of the commonest forms of intoxification. One of
the most potent of the non-protein toxins, tetro
dotoxin, which blocks conduction of action po
tentials in nerves without altering the resting mem
brane potential is the best known of the toxins
involved. The toxin specifically prevents the increase
in sodium conductance that follows partial depolari
zation of the membrane by a stimulating electric
current. It do es not affect the secondary increase in
potassium conduction, demonstrating that this
change in conductance is an independent event and
not a secondary consequence of the primary increase
in sodium conduction. There is evidence that
tetrodotoxin displaces thiamine phosphate and occu
pies its site in the membrane, thus blocking exchange
of potassium for calcium that precedes the increase
in sodium conductance. Block of sodium channels
leads to failure of action poten ti als to propagate
along axons. Sensory neurones are affected first but
at higher doses motor nerves are also blocked leading
to skeletal muscle weakness and ultimately muscle
paralysis and respiratory col1apse[33]. Tetrodotoxin
does not block conduction in smooth muscles in
which the depolarizing current is carried mainly by
ions other than sodium.
Tetrodotoxin s about 100000 times more potent
than cocaine, although it is not used in medicine as
a local anaesthetic. Puffer fish, ciguatera and para
lytic shellfish poisoning cannot be distinguished
clinically and these ha ve been grouped together as
pelagic paralysis [55]. The clnical picture of each is
that of a gastrointestinal illness with associated acute
neurotoxic features such as paraesthesia, ataxia and
muscular weakness. Paradoxical sensations occur
also [55].
A variety of clams and mussels ingest a unicellular
dinoftagellate, Gonyaulux catenella, which produces
saxitoxin which has an action similar to that of
tetrodotoxin. Saxitoxin is responsible for paralyric
shellfish poisoning [9]. Ciguatoxin activates sodium
channels from normal resting potential and produces
an irreversible depolarization [33]. Tetrodotoxin and
saxitoxin can paralyse skeletal muscle directly [33].
There is no specific remedy for poisoning. How
ever, supportive measures can be life saving.
Blue-ringed octopus (found in Australia)
Envenoming produces toxiciry from tetrodotoxin.
Colombian frog
Skin secretions of the brightly coloured Colombian
frog used by natives as arrow and dart poisons
contain batrachotoxin which prevents inactivation of
sodium channels resulting in a massive inftux of

sodium ions and persistent membrane depolari

zation. More than 100 biologically active alkaloids
have been characterized in skin extracts from these
dendrobatid frogs. Pumiliotoxins which block nic
otinic receptor-mediated neuromuscular
transmis
sion, and histrionicotoxins, which block conductance
of acetylcholine receptor-channel complex and shor
tens the time the channel remains open, are a few
[19].
Tick envenoming
Tick paralysis occurs when the tick embeds itself in
the victim's skin and introduces the toxin while it
engorges with blood. The toxin was considered to
cause presynaptic failure to liberate acetylcholine
[24], but subsequent srudies showed reduction in
both amplitude and conduction velocities of mixed
motor and sensory nerves [57]. The view held
currently is that the toxin causes changes in the
terminal part of the motor nerve fibre and failure of
mobilization or release of acetylcholine may be
secondary to a defect in conduction in the motor
axon [22,51].
The weakness sets in about 5 days after attachment
of the tick. The toxin appears to be excreted rapidly
or metabolized when the tick is removed as recovery
is complete, usually 12-24 h after its remo val.
However, there has been one report of death after
removal of a tick.
Tick paralysis has been reported mostly from
Western North America, Eastern United States,
Eastem Australia and British Colombia [64]. The
tick must be detached without being squeezed.
Ventilatory care may be required and an antivenom
is available in Australia.
Conclusion
Animal toxins produce a wide range of physiological
and pharmacological disturbances.
Disorders
of
function at the neuromuscular
junction are of
particular interest [75] and most intoxications re
quire close monitoring and some form of intensive
careo The role of toxins in the advancement of
knowledge of human function is undeniable and
further studies may prove invaluable in developing
new drugs and techniques.
"It is unjust that when you have done
all that a serpent should
you gather our poisons one by one
and break them down to your good"
-Kipling.
Acknowledgements
The help given by Professor A. L. Harvey and Professor D. J.
Warrell, rnembers of the anaesthetic department, QEMH, Tim
Marchant, S. Karalliedde and Lynda Kerr during varying stages
in the preparaton of mis manuscript is gratefully acknowledged.

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