Snake venom is highly modified saliva containing zootoxins that facilitates the immobilization and digestion of prey, and defends against a threat. It is injected by unique fangs after a bite but some species are also able to spit.
The glands that secrete the zootoxins are a modification of the parotid salivary gland found in other vertebrates and are usually situated on each side of the head, below and behind the eye and encapsulated in a muscular sheath. The glands have large alveoli in which the synthesized venom is stored before being conveyed by a duct to the base of channeled or tubular fangs through which it is ejected.
Venoms contain more than 20 different compounds, mostly proteins and polypeptides. A complex mixture of proteins, enzymes, and various other substances with toxic and lethal properties serves to immobilize the prey animal, enzymes play an important role in the digestion of prey, and various other substances are responsible for important but non-lethal biological effects. Some of the proteins in snake venom have very specific effects on various biological functions including blood coagulation, blood pressure regulation, transmission of the nervous or muscular impulse and have been developed for use as pharmacological or diagnostic tools or even useful drugs.
- 1 Chemistry
- 2 Toxins
- 3 Determining venom toxicity (LD50)
- 4 Evolution
- 5 Injection
- 6 Physiological effects
- 7 Use of snake venoms to treat disease
- 8 Immunity
- 9 Traditional Treatments
- 10 See also
- 11 References
- 12 External links
Proteins constitute 90-95% of venom's dry weight and they are responsible for almost all of its biological effects. Among hundreds, even thousands of proteins found in venom, there are toxins, neurotoxins in particular, as well as nontoxic proteins (which also have pharmacological properties), and many enzymes, especially hydrolytic ones. Enzymes (molecular weight 13-150 KDa) make-up 80-90% of viperid and 25-70% of elapid venoms: digestive hydrolases, L-amino acid oxidase, phospholipases, thrombin-like pro-coagulant, and kallikrein-like serine proteases and metalloproteinases (hemorrhagins), which damage vascular endothelium. Polypeptide toxins (molecular weight 5-10 KDa) include cytotoxins, cardiotoxins, and postsynaptic neurotoxins (such as α-bungarotoxin and α-Cobratoxin), which bind to acetylcholine receptors at neuromuscular junctions. Compounds with low molecular weight (up to 1.5 KDa) include metals, peptides, lipids, nucleosides, carbohydrates, amines, and oligopeptides, which inhibit angiotensin converting enzyme (ACE) and potentiate bradykinin (BPP). Inter- and intra-species variation in venom chemical composition is geographical and ontogenic. Phosphodiesterases interfere with the prey's cardiac system, mainly to lower the blood pressure. Phospholipase A2 causes hemolysis by lysing the phospholipid cell membranes of red blood cells. Amino acid oxidases and proteases are used for digestion. Amino acid oxidase also triggers some other enzymes and is responsible for the yellow colour of the venom of some species. Hyaluronidase increases tissue permeability to accelerate absorption of other enzymes into tissues. Some snake venoms carry fasciculins, like the mambas (Dendroaspis), which inhibit cholinesterase to make the prey lose muscle control.
|L-amino-acid oxidase||All species|
|Transferases||Alanine amino transferase|
|Hydrolases||Phospholipase A2||All species|
|Alkaline phosphatase||Bothrops atrox|
|Acid phosphatase||Deinagkistrodon acutus|
|Ribonuclease 1||All species|
|Adenosine triphosphatase||All species|
|Factor-X activator||Viperidae, Crotalinae|
|Lyases||Glucosamine ammonium lyase|
Snake toxins vary greatly in their functions. Two broad classes of toxins found in snake venoms are neurotoxins (mostly found in elapids) and hemotoxins (mostly found in viperids). However, there are exceptions - the venom of the black-necked spitting cobra (Naja nigricollis) consists mainly of hemotoxins, while that of the Mojave rattlesnake (Crotalus scutulatus) is primarily neurotoxic. There are numerous other types of toxin which both elapids and viperids may carry.
|α-neurotoxins||α-Bungarotoxin, α-toxin, erabutoxin, cobratoxin|
|β-neurotoxins||Notexin, ammodytoxin, β-Bungarotoxin, crotoxin, taipoxin|
|Dendrotoxins||Dendrotoxin, toxins I and K|
|Cardiotoxins||y-Toxin, cardiotoxin, cytotoxin|
|Sarafotoxins||Sarafotoxins a, b, and c|
|Hemorrhagins||Phospholipase A2, mucrotoxin A, hemorrhagic toxins a, b, c..., HT1, HT2|
|Structure of a typical chemical synapse|
The beginning of a new impulse:
A) An exchange of ions (charged atoms) across the nerve cell membrane sends a depolarizing current towards the end of the nerve cell (cell terminus).
B) When the depolarizing current arrives at the nerve cell terminus, the neurotransmitter acetylcholine (ACh), which is held in vesicles, is released into the space between the two nerves (synapse). It moves across the synapse to the postsynaptic receptors.
C) ACh binds to the receptors and transfers the signal to the target cell, after a short time it is destroyed by acetylcholinesterase. If multiple stimuli come from the nerve the same thing will happen many more times and then its called a tetanus which is a normal thing for muscles, it's how they work.
These toxins attack cholinergic neurons (those that use ACh as a transmitter) by destroying acetylcholinesterase (AChE). ACh therefore cannot be broken down and stays in the receptor. This causes tetany (involuntary muscle contraction), which can lead to death. The toxins have been called fasciculins since after injection into mice, they cause severe, generalized and long-lasting (5-7 h) fasciculations (rapid muscle contractions).
Dendrotoxins inhibit neurotransmissions by blocking the exchange of positive and negative ions across the neuronal membrane lead to no nerve impulse, thereby paralysing the nerves.
Snake example: mambas
This is a large group of toxins, with over 100 postsynaptic neurotoxins having been identified and sequenced. α-neurotoxins also attack cholinergic neurons. They mimic the shape of the acetylcholine molecule and therefore fit into the receptors → they block the ACh flow → feeling of numbness and paralysis.
Snake examples: king cobra (Ophiophagus hannah) (known as hannahtoxin containing α-neurotoxins), sea snakes (Hydrophiinae) (known as erabutoxin), many-banded krait (Bungarus multicinctus) (known as α-Bungarotoxin), and cobras (Naja spp.) (known as cobratoxin)
Phospholipase is an enzyme that transforms the phospholipid molecule into a lysophospholipid (soap) ==> the new molecule attracts and binds fat and ruptures cell membranes.
Snake example: Okinawan habu (Trimeresurus flavoviridis)
Cardiotoxins are components that are specifically toxic to the heart. They bind to particular sites on the surface of muscle cells and cause depolarisation ==> the toxin prevents muscle contraction. These toxins may cause the heart to beat irregularly or stop beating, causing death.
Hemotoxins cause hemolysis, the destruction of red blood cells (erythrocytes), or induce blood coagulation (clotting).
Snake cytotoxin IPR003572
Determining venom toxicity (LD50)
The potency of the venom of wild snakes varies considerably, even within any single species. This is because of assorted influences such as biophysical environment, physiological status, ecological variables, genetic variation (either adaptive or incidental) and various other molecular- and ecological evolutionary factors. Such variation necessarily is smaller in captive populations in controlled laboratory settings though it cannot be eliminated altogether. However, studies to determine snake venom lethality or potency need to be designed to minimise variability and several techniques have been designed to this end. One approach that is considered particularly helpful is to use 0.1% bovine serum albumin (also known as "Fraction V" in Cohn process) as a diluent in determining LD50 values for various species. It results in far more accurate and consistent median lethal dose (LD50) determinations than for example using 0.1% saline as a diluent. Fraction V produces about 95% purified albumin, which is the dried crude venom. Saline as a diluent consistently produces widely varying LD50 results for nearly all venomous snakes; it produces unpredictable variation in the purity of the precipitate (range from 35-60%). Fraction V is structurally stable because it has seventeen disulfide bonds; it is unique in that it has the highest solubility and lowest isoelectric point of all the major plasma proteins. This makes it the final fraction to be precipitated from its solution. Bovine serum albumin is located in fraction V. The precipitation of albumin is done by reducing the pH to 4.8, which is near the pI of the proteins, and maintaining the ethanol concentration to be 40%, with a protein concentration of 1%. Thus, only 1% of the original plasma remains in the fifth fraction. When the ultimate goal of plasma processing is a purified plasma component for injection or transfusion, the plasma component must be highly pure. The first practical large-scale method of blood plasma fractionation was developed by Edwin J. Cohn during World War II. It is known as the Cohn process (or Cohn method). This process is also known as cold ethanol fractionation as it involves gradually increasing the concentration of ethanol in the solution at 5oC and 3oC. The Cohn Process exploits differences in properties of the various plasma proteins, specifically, the high solubility and low pI of albumin. As the ethanol concentration is increased in stages from 0% to 40% the [pH] is lowered from neutral (pH ~ 7) to about 4.8, which is near the pI of albumin. At each stage certain proteins are precipitated out of the solution and removed. The final precipitate is purified albumin. Several variations to this process exist, including an adapted method by Nitschmann and Kistler that uses less steps, and replaces centrifugation and bulk freezing with filtration and diafiltration. Some newer methods of albumin purification add additional purification steps to the Cohn Process and its variations. Chromatographic albumin processing as an alternative to the Cohn Process emerged in the early 1980s, however, it was not widely adopted until later due to the inadequate availability of large scale chromatography equipment. Methods incorporating chromatography generally begin with cryo-depleted plasma undergoing buffer exchange via either diafiltration or buffer exchange chromatography, to prepare the plasma for following ion exchange chromatography steps. After ion exchange there are generally further chromatographic purification steps and buffer exchange.
However, chromatographic methods for separation started being adopted in the early 1980s. Developments were ongoing in the time period between when Cohn fractionation started being used, in 1946, and when chromatography started being used, in 1983. In 1962, the Kistler & Nistchmann process was created which was a spin-off of the Cohn process. Chromatographic processes began to take shape in 1983. In the 1990s, the Zenalb and the CSL Albumex processes were created which incorporated chromatography with a few variations. The general approach to using chromatography for plasma fractionation for albumin is: recovery of supernatant I, delipidation, anion exchange chromatography, cation exchange chromatography, and gel filtration chromatography. The recovered purified material is formulated with combinations of sodium octanoate and sodium N-acetyl tryptophanate and then subjected to viral inactivation procedures, including pasteurisation at 60 °C. This is a more efficient alternative than the Cohn process for four main reasons: 1) smooth automation and a relatively inexpensive plant was needed, 2) easier to sterilize equipment and maintain a good manufacturing environment, 3) chromatographic processes are less damaging to the albumin protein, and 4) a more successful albumin end result can be achieved. Compared with the Cohn process, the albumin purity went up from about 95% to 98% using chromatography, and the yield increased from about 65% to 85%. Small percentage increases make a difference in regard to sensitive measurements like purity. There is one big drawback in using chromatography, which has to do with the economics of the process. Although the method was efficient from the processing aspect, acquiring the necessary equipment is a big task. Large machinery is necessary, and for a long time the lack of equipment availability was not conducive to its widespread use. The components are more readily available now but it is still a work in progress.
Snake venom consists of many different toxin proteins: these can either have enzymatic activity, which typically assists in digestion, or can be shorter peptides that are used to immobilize prey. Toxin proteins make up many multigene families, and arose from gene recruitment of proteins that do not code for toxins, followed by extensive evolutionary modification. Toxin evolution follows the birth-and-death model of gene families, where duplication followed by functional diversification results in the creation of structurally related proteins that have slightly different functions. It is thought that venom as a way to immobilize prey was beneficial in allowing the uncoupling of feeding system and locomotion, which are coupled in the Haenophidians, which then enabled snakes with venom systems to colonize open areas. Venom continue to evolve as specific toxins are modified to target a specific prey, and it is found that toxins vary according to diet in some species.
The presence of enzymes in snake venom was once believed to be an adaptation to assist digestion. However, studies of the western diamondback rattlesnake (Crotalus atrox), a snake with highly proteolytic venom, show that venom has no impact on the time required for food to pass through the gut.
In the vipers, which have the most highly developed venom delivery apparatus, the venom gland is very large and is surrounded by the masseter or temporal muscle, which consists of two bands, the superior arising from behind the eye, the inferior extending from the gland to the mandible. A duct carries venom from the gland to the fang. In vipers and elapids, this groove is completely closed, forming a hypodermic needle-like tube. In other species, the grooves are not covered, or only partially covered. From the anterior extremity of the gland, the duct passes below the eye and above the maxillary bone, to the basal orifice of the venom fang, which is ensheathed in a thick fold of mucous membrane. By means of the movable maxillary bone hinged to the prefrontal bone and connected with the tranverse bone which is pushed forward by muscles set in action by the opening of the mouth, the fang is erected and the venom discharged through the distal orifice. When the snake bites, the jaws close and the muscles surrounding the gland contract, causing venom to be ejected via the fangs.
Mechanics of biting
Several genera, including Asian coral snakes (Calliophis), burrowing asps (Atractaspis) and night adders (Causus), are remarkable for having exceptionally long venom glands, extending along each side of the body, in some cases extending posterially as far as the heart. Instead of the muscles of the temporal region serving to press out the venom into the duct, this action is performed by those of the side of the body.
There is considerable variability in biting behavior among snakes. When biting, viperid snakes often strike quickly, discharging venom as the fangs penetrate the skin, and then immediately release. Alternatively, as in the case of a feeding response, some viperids (e.g. Lachesis) will bite and hold. A proteroglyph or opisthoglyph may close its jaws and bite or chew firmly for a considerable time.
Mechanics of spitting
Spitting cobras of the genera Naja and Hemachatus, when irritated or threatened, may eject streams or a spray of venom a distance of 4 to 8 feet. These snakes' fangs have been modified for the purposes of spitting: inside the fangs, the channel makes a ninety degree bend to the lower front of the fang. Spitters may spit repeatedly and still be able to deliver a fatal bite.
Spitting is a defensive reaction only. The snakes tend to aim for the eyes of a perceived threat. A direct hit can cause temporary shock and blindness through severe inflammation of the cornea and conjunctiva. Although usually there are no serious results if the venom is washed away immediately with plenty of water, blindness can become permanent if left untreated. Brief contact with the skin is not immediately dangerous, but open wounds may be vectors for envenomation.
There are four distinct types of venom that act on the body differently.
- Proteolytic venom dismantles the molecular structure of the area surrounding and including the bite.
- Hemotoxic venoms act on the heart and cardiovascular system.
- Neurotoxic venom acts on the nervous system and brain.
- Cytotoxic venom has a localized action at the site of the bite.
It is noteworthy that the size of the venom fangs is in no relation to the virulence of the venom.
The effect of the venom of proteroglyphous snakes (sea snakes, kraits, mambas, black snakes, tiger snakes, death adders) is mainly on the nervous system, respiratory paralysis being quickly produced by bringing the venom into contact with the central nervous mechanism which controls respiration; the pain and local swelling which follow a bite are not usually severe.
The bite of all the proteroglyphous elapids, even of the smallest and gentlest, such as the coral snakes, is, so far as known, deadly to humans.
Viper venom (Russell's viper, saw-scaled vipers, bushmasters, rattlesnakes) acts more on the vascular system, bringing about coagulation of the blood and clotting of the pulmonary arteries; its action on the nervous system is not great, no individual group of nerve-cells appears to be picked out, and the effect upon respiration is not so direct; the influence upon the circulation explains the great depression which is a symptom of viperine envenomation. The pain of the wound is severe, and is speedily followed by swelling and discoloration. The symptoms produced by the bite of the European vipers are thus described by Martin and Lamb:
The bite is immediately followed by local pain of a burning character; the limb soon swells and becomes discoloured, and within one to three hours great prostration, accompanied by vomiting, and often diarrhoea, sets in. Cold, clammy perspiration is usual. The pulse becomes extremely feeble, and slight dyspnoea and restlessness may be seen. In severe cases, which occur mostly in children, the pulse may become imperceptible and the extremities cold; the patient may pass into coma. In from twelve to twenty-four hours these severe constitutional symptoms usually pass off; but in the meantime the swelling and discoloration have spread enormously. The limb becomes phlegmonous, and occasionally suppurates. Within a few days recovery usually occurs somewhat suddenly, but death may result from the severe depression or from the secondary effects of suppuration. That cases of death, in adults as well as in children, are not infrequent in some parts of the Continent is mentioned in the last chapter of this Introduction.
The Viperidae differ much among themselves in the toxicity of their venom. Some, such as the Indian Russell's viper (Daboia russelli) and saw-scaled viper (Echis carinatus); the American rattlesnakes (Crotalus spp.), bushmasters (Lachesis spp.) and lanceheads (Bothrops spp.); and the African adders (Bitis spp.), night adders (Causus spp.), and horned vipers (Cerastes spp.), cause fatal results unless a remedy is speedily applied. The bite of the larger European vipers may be very dangerous, and followed by fatal results, especially in children, at least in the hotter parts of the Continent; whilst the small meadow viper (Vipera ursinii), which hardly ever bites unless roughly handled, does not seem to be possessed of a very virulent venom, and, although very common in some parts of Austria and Hungary, is not known to have ever caused a serious accident.
Biologists had long known that some snakes had rear fangs, 'inferior' venom injection mechanisms that might immobilize prey; although a few fatalities were on record, until 1957 the possibility that such snakes were deadly to humans seemed at most remote. The deaths of two prominent herpetologists from African colubrid bites changed that assessment, and recent events reveal that several other species of rear-fanged snakes have venoms that are potentially lethal to large vertebrates.
Boomslang (Dispholidus typus) and twig snake (Thelotornis spp.) venom are toxic to blood cells and thin the blood (hemotoxic, hemorrhagic). Early symptoms include headaches, nausea, diarrhea, lethargy, mental disorientation, bruising and bleeding at the site and all body openings. Exsanguination is the main cause of death from such a bite.
The boomslang's venom is the most potent of all rear-fanged snakes in the world based on LD50. Although its venom may be more potent than some vipers and elapids, it causes fewer fatalities owing to various factors (for example, the fangs' effectiveness is not high compared with many other snakes: the venom dose delivered is low, and boomslangs are generally less aggressive in comparison to other venomous snakes such as cobras and mambas).
Experiments made with the secretion of the parotid gland of Rhabdophis and Zamenis have shown that even aglyphous snakes are not entirely devoid of venom, and point to the conclusion that the physiological difference between so-called harmless and venomous snakes is only one of degree, just as there are various steps in the transformation of an ordinary parotid gland into a venom gland or of a solid tooth into a tubular or grooved fang.
Use of snake venoms to treat disease
Given that snake venom contains many biologically ingredients, some may be useful to treat disease.
For instance, Phospholipases type A2 (PLA2s) from the Tunisian vipers Cerastes cerastes and Macrovipera lebetina has been found to have anti-tumor activity. Anti-cancer activity has been also reported for other compounds in snake venom.
Phospholipases A2 hydrolyze phospholipids and thus could act on bacterial cell surfaces, providing novel antimicrobial (antibiotic) activities.
The analgesic (pain-killing) activity of many snake venom proteins has been long known. The main challenge, however, is to deliver protein to the nerve cells as proteins usually are not applicable as pills.
The question whether individual snakes are immune to their own venom has not yet been definitively settled, though there is a known example of a cobra which self-envenomated, resulting in a large abscess requiring surgical intervention but showing none of the other effects that would have proven rapidly lethal in prey species or humans. Furthermore, certain harmless species, such as the North American common kingsnake (Lampropeltis getula) and the Central and South American mussurana (Clelia spp.), are proof against the venom of the crotalines which frequent the same districts, and which they are able to overpower and feed upon. The chicken snake (Spilotes pullatus) is the enemy of the Fer-de-Lance (Bothrops caribbaeus) in St. Lucia, and it is said[by whom?] that in their encounters the chicken snake is invariably the victor. Repeated experiments have shown the European grass snake (Natrix natrix), not to be affected by the bite of European adder (Vipera berus) and European asp (Vipera aspis), this being due to the presence, in the blood of the harmless snake, of toxic principles secreted by the parotid and labial glands, and analogous to those of the venom of these vipers. Several North American species of rat snakes as well as king snakes have proven to be immune or highly resistant to the venom of rattlesnake species.
Among other animals
The hedgehog (Erinaceidae), the mongoose (Herpestidae), the honey badger (Mellivora capensis), the secretarybird (Sagittarius serpentarius) and a few other birds that feed on snakes are known to be immune to a dose of snake venom. Whether the pig may be considered so is still uncertain, although it is well known that, owing to its subcutaneous layer of fat, it is often bitten without ill effect. The garden dormouse (Eliomys quercinus) has recently been added to the list of animals refractory to viper venom. Some populations of California ground squirrel (Otospermophilus beecheyi) are at least partially immune to rattlesnake venom as adults.
The acquisition of human immunity against snake venom is one of the oldest forms of vaccinology known to date (about AD 60, Psylli Tribe). Research into development of vaccines that will lead to immunity is ongoing. Bill Haast, owner and director of the Miami Serpentarium injected himself with snake venom during most of his adult life, in an effort to build up an immunity to a broad array of venomous snakes. It is a practice known as mithridatism. Haast lived to age 100, and survived a reported 172 snake bites. He donated his blood to be used in treating snake-bite victims when a suitable anti-venom was not available. More than twenty of those individuals recovered.
The World Health Organization estimates that 80% of the world’s population depends on traditional medicine for their primary health care needs. Methods of traditional treatment of snake bite, although of questionable efficacy and perhaps even harmful, are nonetheless relevant.
Plants used to treat snakebites in Trinidad and Tobago are made into tinctures with alcohol or olive oil and kept in rum flasks called 'snake bottles'. Snake bottles contain several different plants and/or insects. The plants used include the vine called monkey ladder (Bauhinia cumanensis or Bauhinia excisa, Fabaceae) which is pounded and put on the bite. Alternatively a tincture is made with a piece of the vine and kept in a snake bottle. Other plants used include: mat root (Aristolochia rugosa), cat's claw (Pithecellobim unguis-cati), tobacco (Nicotiana tabacum), snake bush (Barleria lupulina), obie seed (Cola nitida), and wild gri gri root (Acrocomia aculeata). Some snake bottles also contain the caterpillars (Battus polydamas, Papilionidae) that eat tree leaves (Aristolochia trilobata). Emergency snake medicines are obtained by chewing a three-inch piece of the root of bois canôt (Cecropia peltata) and administering this chewed-root solution to the bitten subject (usually a hunting dog). This is a common native plant of Latin America and the Caribbean which makes it appropriate as an emergency remedy. Another native plant used is mardi gras (Renealmia alpinia)(berries), which are crushed together with the juice of wild cane (Costus scaber) and given to the bitten. Quick fixes have included applying chewed tobacco from cigarettes, cigars or pipes. Making cuts around the puncture or sucking out the venom had been thought helpful, in the past, but this course of treatment is now strongly discouraged.
Especially noteworthy is progress regarding the defensive reaction by which the blood may be rendered proof against their effect, by processes similar to vaccination—antipoisonous serotherapy.
The studies to which we allude have not only conduced to a method of treatment against snake-bites, but have thrown a new light on the great problem of immunity.
They have shown that the antitoxic sera do not act as chemical antidotes in destroying the venom, but as physiological antidotes; that, in addition to the venom glands, snakes possess other glands supplying their blood with substances antagonistic to the venom, such as also exist in various animals refractory to snake venom, the hedgehog and the mongoose for instance.
Regional venom specificity
Unfortunately, the specificity of the different snake venoms is such that, even when the physiological action appears identical, serum injections or graduated direct inoculations confer immunity towards one species or a few allied species only.
Thus, a European in Australia who had become immune to the venom of the deadly Australian tiger snake (Notechis scutatus), manipulating these snakes with impunity, and was under the impression that his immunity extended also to other species, when bitten by a lowland copperhead (Austrelaps superbus), an allied elapine, died the following day.
In India, the serum prepared with the venom of monocled cobra Naja kaouthia has been found to be without effect on the venom of two species of kraits (Bungarus), Russell's viper (Daboia russelli), saw-scaled viper (Echis carinatus), and Pope's pit viper (Trimeresurus popeorum). Russell's viper serum is without effect on colubrine venoms, or those of Echis and Trimeresurus.
Antivenom snakebite treatment must be matched as the type of envenomation that has occurred.
These are not effective against coral snake envenomation, which requires a specific antivenom to their neurotoxic venom.
This article is based on the 1913 book The Snakes of Europe, by G. A. Boulenger, which is now in the public domain in the United States (and possibly elsewhere). Because of its age, the text in this article should not necessarily be viewed as reflecting the current knowledge of snake venom.
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- Jonassen I, Collins JF, Higgins DG (August 1995). "Finding flexible patterns in unaligned protein sequences". Protein Sci. 4 (8): 1587–95. doi:10.1002/pro.5560040817. PMC 2143188. PMID 8520485.
- Shaw IC (2007). "Chapter 19: Snake Toxins". In Waring RH, Steventon GB, Mitchell SC. Molecules of Death (Second ed.). River Edge, N.J: Imperial College Press. pp. 329–344. ISBN 1-86094-815-4.