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Snake venom is the poison fluid normally secreted by venomous snakes when biting. It is produced in the glands, and injected by the fangs. Snake venom is used to immobilize and/or kill prey, and used secondarily in defence. It is a clear, viscous fluid of amber or straw colour.
There are two main types of venom produced by snakes, containing primarily either:
*Neurotoxins - these attack the nervous system.
*Hemotoxins - these attack the circulatory system.
While most snakes' venom contains primarily either one or the other, there are some snakes which have a combination of both in their venom.
The snake's poison is a combination of biologically active agents: ferments or enzymes as proteases and hyaluronidase (including 20 digestive enzymes), metal ions, biogenic amines, lipids, free amino acids, and more than 80 large and small proteins and polypeptides that have only been partially identified. While it is a complex recipe, snake venom is made up of mainly proteins and enzymes. The primary constituents of snake venom are as follow:
*Enzymes - Spur physiologically disruptive or destructive processes.
*Proteolysins - Dissolve cells and tissue at the bite site, causing local pain and swelling.
*Cardiotoxins - Variable effects, some depolarise cardiac muscles and alter heart contraction, causing heart failure.
*Harmorrhagins - Destroy capillary walls, causing haemorrhages near and distant from the bite.
*Coagulation - Retarding compounds prevent blood clotting.
*Thromboses - Coagulate blood and foster clot formation throughout the circulatory system.
*Haemolysis - Destroy red blood cells.
*Cytolysins - Destroy white blood cells.
*Neurotoxins - Block the transmission of nerve impulses to muscles, especially those associated with the diaphragm and breathing.
Every snake has a different amount of the aforementioned agents its venom, hence the differing levels of toxicity.
Throughout this report, the examination of the venom of only the most deadly snake in the world: the 'Inland Taipan', will be carried out. The report contains an analysis of the venom of the Inland Taipan, along with its medical uses.
The Inland Taipan
The Oxyuranus microlepidotus (inland taipan) is a member of the family Elapidae (elapid snakes), and belongs to the Genus Oxyuranus. The back, sides and tail are of a buff brown colour, and it's eyes are of average size, with a blackish brown iris. It is found only in the central, and central western desert regions of Australia.
Although the inland taipan has the most lethal venom of any snake in the world, it is placid and shy. However, if cornered and/or provoked, it holds it's body in low, flat, S-shaped curves with it's head pointed straight at the disturber. It usually makes a single bite, or a few fast ones.
The venom of the inland taipan is primarily neurotoxic. However, while the myotoxic and procoagulative proteins are present to a lesser degree, they too contribute to the bite pathology.
The neurotoxins contained in the inland taipan's venom are as follow:
*Taipoxin - presynaptic neurotoxin, phospholipase A2 based,
moderately acidic sialo-glycoprotein, MW 45,600, as a
ternary complex 1:1:1 with a , b , g subunits. a and b
subunits are 120 amino acids long, with 7 disulphide
bridges. g subunit has 135 amino acids and 8disulphide
bridges. Only the very basic (pI <10) g-subunit has lethal
neurotoxicity. LD50 of complete molecule is 2 mg/kg (IV
mouse). 17% of venom.
*Paradoxin - presynaptic neurotoxin, phospholipase A2 based,
essentially identical to taipoxin. It accounts for 12% of
crude venom, is a sialo-glycoprotein with three subunits and
has an LD50 of 2 mg/kg (IV mouse). Amino acid analysis of
paradoxin and taipoxin, both in whole form and as subunits,
shows close homology.
*O. scutellatus fraction III - minimal data. Presumed
postsynaptic neurotoxin. LD50 100 mg/kg (IV mouse). 47% of
*O. scutellatus fraction IV - minimal data. Presumed
postsynaptic neurotoxin. LD50 100 mg/kg (IV mouse). MW
approximately 8,000. 10% of venom.
Composition of this mixture may not be uniform throughout all populations of taipans.
The presynaptic constituents are much more potent than those which are postsynaptic. They work by affecting the terminal axon. On reaching the neuromuscular junction the presynaptic neurotoxin must bind to the terminal axon membrane, damage the membrane, and then exert its toxin effects. Initially this may cause release of acetylcholine (Ach), with some muscle twitching, rarely noticed clinically, before destroying vesicles and blocking further Ach release. This process takes from 60 to 80 minutes. Following the process, the neuromuscular block becomes detectable, and quickly becomes complete paralysis. This is associated with a reduction in cholinergic synaptic vesicle number, fusion of vesicles, and damage of intracellular organelles such as mitochondria. There is an increase in the level of free calcium in the nerve terminal, so the neurotransmitter Ach appears to be progressively removed or made unavailable for release, which causes paralysis.
The postsynaptic neurotoxins cause blockade of the acetylcholine receptor on the muscle end-plate at the neuromuscular junction by binding to, or adjacent to the acetylcholine receptor protein on the muscle end plate, effectively blocking the signal arrival at the muscle. They can begin acting immediately after the reach the neuromuscular junction, so they cause paralysis before the presynaptic neurotoxins do. As this action is extracellular, these toxins are more readily reached by antivenom.
Neurotoxins also neutralize the enzyme Acetylcholinesterase, which brings the nervous system to a halt, causing paralysis. Diisopropylphosphorofluoridate is one reagent which has this deactivating property, and is present in the venom of the inland taipan.
Denrotoxins are another class of neurotoxin, which acts on the neuromuscular junction. They are presynaptic, but are different from those discussed earlier. They block some potassium channels on the terminal axon membrane, which causes an over-release of Ach, resulting in initial stimulation, then blockade, causing flaccid paralysis.
Procoagulants have been isolated from O. scutellatus venom and O. microlepidotus venom. They are proteins, with a MW of about 200,000 D, and achieve their action in a manner analogous to factor Xa, causing conversion of prothrombin, through intermediates, to thrombin. However, they are direct prothrombin converters, working largely independent of cofactors in the absence of factor V, calcium and phospholipid. The thrombin product then converts fibrinogen to fibrin clots in vitro. [Walker et al, 1980, Speijer et al, 1986]
In human envenomation there is widespread consumption of fibrinogen resulting in defibrination and hypocoagulable blood. Any damage to blood vessels then causes increased bleeding, although spontaneous bleeding is not often seen. Usually platelets are not consumed, but factors V, VIII, Protein C and plasminogen all show acute reductions in human envenomation. While major clots are not seen in man, some fibrin cross linkage and stabilisation does occur in vivo, as XDP levels rise sharply in human envenomation. [White 1983c; White 1987c; White unpublished data]
The procoagulation toxins which activate the prothombin processes remain unknown. It is thought that these unknown components, which promote the formation of thrombin from prothrombin, without even the need of the cofactors calcium, factor V or phospholipids. As these cofactors are replaced by the unknown component, the production of thrombin is accelerated. As the clotting of blood requires the formation of fibrin, which is made from thrombin, to occur, the acceleration of thrombin production in turn accelerates fibrin clotting; the remainder fibrinogen molecule, from the splitting action of thrombin, polymerises to form insoluble fibrin; the structure of the clot. Added strength is given to these fibrin strands through covalent bonds between adjacent fibrin monomers.
The effects that are induced by due to the action of procoagulative venom on humans include vomiting or the expectoration of blood.
In the inland taipan, if antivenom is not given to the victim, the coagulopathy will usually be prolonged. Major haemorrhage associated with snakebite coagulopathy is not very common, nor is it rare, with intracranial bleeding a concern.
Myotoxins interact with calcium-activated Ca 2+ -ATPase (CaATPase), a membrane protein found in the muscle sarcoplasmic reticulum, causing vacolation and eventual destruction of skeletal muscle. CaATPase is responsible for maintaining calcium balance within the muscle cell.
The Calcium Channels are opened by an electrical nerve signal. The Ca ions enter the Cytoplasm, releasing neurotransmitters. However, when myotoxins are present, they interfere with the opening of the Ca channel, reducing the amount of neurotransmitters released, slowing down the nervous system.
In the muscle cell, Calcium is constantly being pumped out of the Ca-pump. However, myotoxins can interfere with this, stopping the regeneration of Ca inside the cell, thus stopping the release of Ca. With the absence of Ca in the cell, chemical messages are unable to cross the synapse (because ordinarily, the Ca carries the message across). This leads to weakness and paralysis of the prey.
Another way that the myotoxins from the venom of the inland taipan cause paralysis are through the break up of the phospholipid compounds of the surface membranes of muscle cells. It is the enzyme Phospholipase A2 which destroys the muscle tissue. This enzyme exhibits two separate actions: a non-lethal esterase activity and a toxic neurological activity. The phospholipase in the venom of the inland taipan reacts in the form of a hydrolysis reaction.
In this way, the myotoxic effects of paralysis and weakness are caused.
Venom is produced by a pair of large venom glands, situated on either side of the head. The snake delivers its venom by injecting it with fans; teeth with a canal through the centre, through which venom flows.
Some snakes spit their venom, although this will not be discussed as the inland taipan is not capable of this.
Antivenom is a serum that is commercially produced to neutralize the effects of envenomation by venomous snakes. The fresh snake venom used to produce antivenom is obtained either by manually milking a sinkae or by electrical stimulation. Venom is extracted from captive snakes every twenty or thirty days. In manual milking, the snake is held behind its head and induced to bite a thin rubber diaphragm covering a collecting vessel while the handler applies pressure to the snake's venom glands. The pressure is maintained until no more venom is discharged. In electrical stimulation, electrodes are touched to the opposite sides of the snake's head, causing the muscles around the venom gland to contract, expelling venom into a collection containe . The venom is freeze-dried (the preferred method), or dried with the help of a drying agent or a vacuum. [R.Zug " Carl H. Ernst " Harrison's Principles Of Internal Medicine]
Venom as a Medicine
Snake venom has great potential use as a medicine, because of all the compounds it contains, and their specific actions. In Asia, South America, and Europe, components of snake venom are used to treat blood disorders. Snake venom as a whole is not used, but the individual compounds are used.
Two analgesics derive from cobra venom: Cobroxin is used like morphine to block nerve transmission, and Nyloxin reduces severe arthritis pain. Arvin, an extract of the Malayan pitviper (Calloselasma), is an effective anticoagulant (it inhibits the formation of blood cloths).
Venom compounds are also used in research in such fields as Physiology, biochemistry, and immunology. By retarding or accelerating a biochemical or cellular process, venom components allow researchers to examine the process and to develop drugs to counter malfunctions.
Diseases for which snake venoms have been used in research include nerve diseases, such as epilepsy, multiple sclerosis, myasthenia gravis (Lou Gehrig's disease), Parkinson's disease, and poliomyelitis; musculoskeletal disease, including arthritis and rheumatism; cardiovascular disease , such as hypotension, hypertension, angina, and cardiac arrhythmias, and visual disorders, including neuritis, conjunctivitis, and cataracts. [R. Zug " Carl H. Ernst " Harrison]
The procoagulants in the venom of the inland taipan are used to activate prothrombin to alpha thrombin. The anticoagulants are used to prevent interference of immunoglobins which interfere with phospholipid dependent in vitro coagulation tests.
Considering that the components of snake venom are still largely unknown, there is great possibility for more medical uses of these compounds.
Snake venom consists of many compounds, although the main constituents are proteins and enzymes. These poisons cause muscle paralysis, internal bleeding, and degeneration of muscle tissues.
Because we do not yet have a full understanding of the biochemistry of snake venom, the medical uses of its compounds go largely untapped. However, this will soon change, as the research into snake venom is expanding, especially in Australia.
*Chamber's Biology Dictionary [1990, Peter. M.B. Walker]
*Biochemistry [1978, A. L. Lehninger]
*McGraw-Hill Encyclopaedia of Science and Technology [1997, The Lakeside Press]
*Venoms " Victims [1988, J. Pearn " J. Covacevich, Queensland Museum and Ampion Press]
*Encyclopaedia of Life Sciences [1996, Marshall Cavendish Corp]
overview snake venom poison fluid normally secreted venomous snakes when biting produced glands injected fangs snake venom used immobilize kill prey used secondarily defence clear viscous fluid amber straw colour there main types venom produced snakes containing primarily either neurotoxins these attack nervous system hemotoxins these attack circulatory system while most snakes contains primarily either other there some which have combination both their snake poison combination biologically active agents ferments enzymes proteases hyaluronidase including digestive enzymes metal ions biogenic amines lipids free amino acids more than large small proteins polypeptides that have only been partially identified while complex recipe made mainly proteins enzymes primary constituents follow spur physiologically disruptive destructive processes proteolysins dissolve cells tissue bite site causing local pain swelling cardiotoxins variable effects some depolarise cardiac muscles alter heart contraction causing heart failure harmorrhagins destroy capillary walls causing haemorrhages near distant from bite coagulation retarding compounds prevent blood clotting thromboses coagulate blood foster clot formation throughout circulatory system haemolysis destroy blood cells cytolysins destroy white cells neurotoxins block transmission nerve impulses muscles especially those associated with diaphragm breathing every different amount aforementioned agents hence differing levels toxicity throughout this report examination only most deadly world inland taipan will carried report contains analysis inland taipan along with medical uses inland taipan oxyuranus microlepidotus member family elapidae elapid belongs genus oxyuranus back sides tail buff brown colour eyes average size with blackish brown iris found only central central western desert regions australia although most lethal world placid however cornered provoked holds body flat shaped curves head pointed straight disturber usually makes single bite fast ones primarily neurotoxic however while myotoxic procoagulative proteins present lesser degree they contribute pathology neurotoxins contained follow taipoxin presynaptic neurotoxin phospholipase based moderately acidic sialo glycoprotein ternary complex subunits subunits amino acids long disulphide bridges subunit amino acids disulphide bridges very basic subunit lethal neurotoxicity complete molecule mouse paradoxin presynaptic neurotoxin phospholipase based essentially identical taipoxin accounts crude sialo glycoprotein three subunits mouse acid analysis paradoxin taipoxin both whole form shows close homology scutellatus fraction minimal data presumed postsynaptic neurotoxin mouse scutellatus fraction minimal data presumed postsynaptic approximately http inchem documents pims animal composition this mixture uniform throughout populations taipans presynaptic constituents much more potent than those which postsynaptic they work affecting terminal axon reaching neuromuscular junction must bind terminal axon membrane damage membrane then exert toxin effects initially this cause release acetylcholine some muscle twitching rarely noticed clinically before destroying vesicles blocking further release process takes from minutes following process neuromuscular block becomes detectable quickly becomes complete paralysis associated reduction cholinergic synaptic vesicle number fusion vesicles damage intracellular organelles such mitochondria there increase level free calcium nerve terminal neurotransmitter appears progressively removed made unavailable release which causes paralysis cause blockade acetylcholine receptor muscle plate neuromuscular junction binding adjacent acetylcholine receptor protein muscle plate effectively blocking signal arrival they begin acting immediately after reach junction cause paralysis before action extracellular these toxins more readily reached antivenom also neutralize enzyme acetylcholinesterase brings nervous halt diisopropylphosphorofluoridate reagent deactivating property present denrotoxins another class acts different from those discussed earlier block potassium channels axon membrane causes over resulting initial stimulation then blockade flaccid procoagulants procoagulants have been isolated scutellatus microlepidotus about achieve their action manner analogous factor conversion prothrombin through intermediates thrombin however direct prothrombin converters working largely independent cofactors absence factor calcium phospholipid thrombin product then converts fibrinogen fibrin clots vitro walker speijer human envenomation widespread consumption fibrinogen resulting defibrination hypocoagulable damage vessels causes increased bleeding although spontaneous bleeding often seen usually platelets consumed factors viii protein plasminogen show acute reductions human envenomation major clots seen fibrin cross linkage stabilisation does occur vivo levels rise sharply human envenomation white white unpublished data procoagulation toxins activate prothombin processes remain unknown thought that unknown components promote formation thrombin prothrombin without even need cofactors calcium factor phospholipids cofactors replaced unknown component production accelerated clotting requires formation fibrin made occur acceleration production turn accelerates clotting remainder fibrinogen molecule splitting action polymerises form insoluble structure clot added strength given strands through covalent bonds between adjacent monomers effects that induced procoagulative humans include vomiting expectoration antivenom given victim coagulopathy will usually prolonged major haemorrhage associated snakebite coagulopathy very common rare intracranial bleeding concern myotoxins myotoxins interact activated atpase caatpase protein found sarcoplasmic reticulum vacolation eventual destruction skeletal caatpase responsible maintaining balance within cell channels opened electrical nerve signal ions enter cytoplasm releasing neurotransmitters when myotoxins present interfere opening channel reducing amount neurotransmitters released slowing down nervous cell constantly being pumped pump interfere stopping regeneration inside cell thus stopping absence chemical messages unable cross synapse because ordinarily carries message across leads weakness prey another through break phospholipid compounds surface membranes enzyme phospholipase destroys tissue enzyme exhibits separate actions lethal esterase activity toxic neurological activity reacts form hydrolysis reaction myotoxic weakness caused medical uses produced pair large glands situated either side head delivers injecting fans teeth canal centre flows spit their although will discussed capable antivenom serum commercially neutralize venomous fresh used produce obtained manually milking sinkae electrical stimulation extracted captive every twenty thirty days manual milking held behind head induced thin rubber diaphragm covering collecting vessel handler applies pressure glands pressure maintained until discharged electrical stimulation electrodes touched opposite sides muscles around gland contract expelling into collection containe freeze dried preferred method dried help drying agent vacuum carl ernst harrison principles internal medicine medicine great potential medicine because compounds contains specific actions asia south america europe components treat disorders whole individual analgesics derive cobra cobroxin like morphine transmission nyloxin reduces severe arthritis pain arvin extract malayan pitviper calloselasma effective anticoagulant inhibits cloths also research such fields physiology biochemistry immunology retarding accelerating biochemical cellular process components allow researchers examine develop drugs counter malfunctions diseases venoms been research include diseases such epilepsy multiple sclerosis myasthenia gravis gehrig disease parkinson disease poliomyelitis musculoskeletal disease including arthritis rheumatism cardiovascular hypotension hypertension angina cardiac arrhythmias visual disorders including neuritis conjunctivitis cataracts carl ernst harrison procoagulants activate alpha anticoagulants prevent interference immunoglobins interfere phospholipid dependent vitro coagulation tests considering still largely great possibility medical uses conclusion consists many main constituents poisons internal degeneration tissues because full understanding biochemistry largely untapped soon change research into expanding especially australia bibliography roms encyclopaedia britannica encarta webster world book books chamber biology dictionary peter walker biochemistry lehninger mcgraw hill encyclopaedia science technology lakeside press venoms victims pearn covacevich queensland museum ampion press encyclopaedia life sciences marshall cavendish corp websites users whitters paedm clintox cslavh html aqua animals species venfaq html reptileallsorts bites pharmacology unimelb pharmwww avruweb snakebi kingsnake toxinology oxyuranus html inchem documents pims animal worthington biochem manual kordia pentapharm snavenenz snavenenz coloherp news mohiss poison covnomco ayurtoxicology neuroguide ache lycoming newman courses acetylcholinesterase weizmann jsgrp ache ribbon itech jkaplan zootech course materials herplec mysite mweb residents toxins
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