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The Gila monster (Heloderma suspectum) and the beaded lizards (Heloderma horridum) are far less dangerous than is generally believed. Their venom is transferred from venom glands in the lower jaw through ducts that discharge their 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, a bradykinin-releasing substance, helodermin, gilatoxin, and low proteolytic as well as high-hyaluronidase activities. Helotherime, a 25-kDa protein, appears to inhibit calcium ion influx from the sarcoplasmic reticulum. The 35 amino acid peptide helodermin produces hypotension by activating potassium channels in vascular smooth muscle. The clinical presentation of a helodermatid bite can include pain, edema, hypotension, nausea, vomiting, weakness, and diaphoresis.
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Among the more than 2700 species of snakes, about 20 percent are considered to be venomous. Venomous snakes primarily belong to the following families: Viperidae (vipers), Elapidae, Atractaspidae, and Colubridae.
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These venoms are complex mixtures: proteins and peptides, consisting of both enzymatic and nonenzymatic compounds, making up over 90 percent of the dry weight of the venom. Snake venoms also contain inorganic cations such as sodium, calcium, potassium, magnesium, and small amounts of zinc, iron, cobalt, manganese, and nickel. Some snake venoms also contain glycoproteins, lipids, and biogenic amines, such as histamine, serotonin, and neurotransmitters.
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A simplistic classification of snake venoms would group toxin components as neurotoxins, coagulants, hemorrhagins, hemolytics, myotoxins, cytotoxins, and nephrotoxins. Neurotoxins produce neuromuscular paralysis ranging from dizziness to ptosis; to ophthalmoplegia, flaccid facial muscle paralysis, and inability to swallow; to paralysis of larger muscle groups; and finally to paralysis of respiratory muscles and asphyxiation. Coagulants may have initial procoagulant action that uses up clotting factors leading to bleeding. Coagulants may directly inhibit normal clotting at several places in the clotting cascade or via inhibition of platelet aggregation. In addition, some venom components may damage the endothelial lining of blood vessels leading to hemorrhage. Bite victims may show bleeding from nose or gums, the bite site, and in saliva, urine, and stools. Myotoxins can directly impact muscle contraction leading to paralysis or cause rhabdomyolysis or the breakdown of skeletal muscle. Myoglobinuria, or a dark brown urine, and hyperkalemia may be noted. Cytotoxic agents have proteolytic or necrotic properties leading to the breakdown of tissue. Typical signs include massive swelling, pain, discoloration, blistering, bruising, and wound weeping. Sarafotoxins, which are found only in burrowing asps of Afro-Arabia, cause coronary artery constriction, reduced coronary blood flow, angina, and myocardial infarction. Finally, nephrotoxins can cause direct damage to kidney structures, leading to bleeding, damage to several parts of the nephron, tissue oxygen deprivation, and renal failure.
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Snake venoms contain at least 26 enzymes, although no single snake venom contains all of them (Figure 26–1). Proteolytic enzymes, also known as peptide hydrolases, proteases, endopeptidases, peptidases, and proteinases, catalyze the breakdown of tissue proteins. Multiple proteolytic enzymes may be in a single venom. Metals are involved in the activity of certain proteases and phospholipases.
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The crotalid venoms examined so far appear to be rich in proteolyticenzyme activity. Viperid venoms have lesser amounts, whereas elapid and sea snake venoms have little or no proteolytic activity. Venoms that are rich in proteinase activity are associated with marked tissue destruction.
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Collagenase activity, a specific proteinase that digests collagen, 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 proteins.
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Hyaluronidase catalyzes the cleavage of internal glycoside bonds in certain acid mucopolysaccharides, thereby decreasing the viscosity of connective tissues, thus allowing other fractions of venom to penetrate the tissues.
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Arginine ester hydrolase 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. 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.
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Thrombin-like enzymes are found in significant amounts in the venoms of the Crotalidae and Viperidae, whereas those of 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. The proteolytic action of thrombin and thrombin-like snake venom enzymes is compared in Table 26–4 for several species (ancrod from Calloselasma rhodostoma, batroxobin from Bothrops moojeni, crotalase from Crotalus adamanteus, gabonase from Bitis gabonica, and venzyme from Agkistrodon contortrix).
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PLA2, which catalyzes the Ca2+-dependent hydrolysis of the 2-acyl ester bond producing free fatty acids and lysophospholipid, is widely distributed in the venoms of elapids, vipers, crotalids, sea snakes, atractaspids, and several colubrids. PLA2 interact with other toxins in venom, often resulting in synergistic reactions. Although mammalian PLA2s are nontoxic, the snake venom enzymes differ widely in their pharmacologic properties.
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Phosphomonoesterase (phosphatase) is found in the venoms of all families of snakes except colubrids. It has the properties of an orthophosphoric monoester phosphohydrolase. There are two nonspecific phosphomonoesterases; many venoms contain both acid and alkaline phosphatases, whereas other venoms contain one or the other.
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Phosphodiesterase, found in the venoms of all families of poisonous snakes, is an orthophosphoric diester phosphohydrolase that attacks DNA, RNA, and derivatives of arabinose.
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There are other enzymes for which their toxicologic contribution to snake venoms is not understood. These include acetylcholinesterase, RNase, DNase, 5′-nucleotidase, nicotinamide adenine dinucleotide (NAD) nucleotidase, l-amino acid, and lactate dehydrogenase.
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More than 80 snake venom polypeptides are low-molecular-weight proteins and have toxic actions. Erabutoxin a, erabutoxin b, alpha-cobratoxin, crotactin, and crotamine are examples of neurotoxins. Disintegrins are short cysteine-rich polypeptides that exhibit affinities for many ligand receptors. The mycotoxins can induce skeletal muscle spasms and paralysis by altering sodium channel function.
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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 pulmonary 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; and the kind of treatment. 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 clinical problem in North American crotalid bites.
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The treatment of bites by venomous snakes is 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 venomous snake ends in an envenomation. 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.
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Snake Venom Evolution
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Considerable efforts are being expended to examine the complex process by which snake venom components are thought to have changed over the years. In general, the toxins from ancestral proteins that were constructed of dense networks of cysteine cross-linkages are considered among the most diverse today in terms of toxicologic insult.