Snake bite

SNAKE BITESNAKE BITE

• • NeurotoxinNeurotoxin producingproducing snakessnakes

Elapinae: represented by the five genera Elapinae: represented by the five genera Naja, Naja, Bungarus, Ophiophagus, MaticoraBungarus, Ophiophagus, Maticora and and CalliophisCalliophis

Banded krait (Banded krait (Bungarus fasciatusBungarus fasciatus))

– – Malayan krait (Malayan krait (Bungarus candidusBungarus candidus))

– – Red-headed krait (Red-headed krait (Bungarus flaviceps)Bungarus flaviceps)

Mojave rattlesnakeMojave rattlesnake

Coral snakes Coral snakes

venomvenom

The main toxins in the venoms of The main toxins in the venoms of elapid snakes (cobras, kraits and elapid snakes (cobras, kraits and sea snakes) include: sea snakes) include:

1.1. polypeptide postsynaptic polypeptide postsynaptic neurotoxins, neurotoxins,

2.2. cardiotoxins and cardiotoxins and

3.3. phospholipases A phospholipases A

MECHANISM OF ACTIONMECHANISM OF ACTION It takes about 10 minutes for the It takes about 10 minutes for the venomvenom to affect to affect

the nervous system.the nervous system.

Most neurotoxins in snake venoms Most neurotoxins in snake venoms are too large to are too large to cross the cross the blood-brain barrierblood-brain barrier, and so they usually , and so they usually exert their effects on the exert their effects on the peripheralperipheral nervous system nervous system rather than directly on the brain and spinal cord.rather than directly on the brain and spinal cord.

The neurotoxic effects are mainly at the The neurotoxic effects are mainly at the postsynaptic level of the neuromuscular junction postsynaptic level of the neuromuscular junction where the neurotoxins block acetylcholine where the neurotoxins block acetylcholine receptorsreceptors, thereby producing muscular paralysis , thereby producing muscular paralysis and respiratory failure and respiratory failure

Acetylcholine ReceptorsAcetylcholine Receptors

Acetylcholine has two modes of action, Acetylcholine has two modes of action, a a nicotinenicotine-like (nicotinic) or-like (nicotinic) or a a muscarinemuscarine-like (muscarinic) action, -like (muscarinic) action,

with the former blocked by with the former blocked by curarecurare and and

the later by the later by atropineatropine. . Nicotinic acetylcholine receptors are found primarily at Nicotinic acetylcholine receptors are found primarily at

neuromuscular junctionsneuromuscular junctions while while muscarinic acetylcholine receptors are found primarily in muscarinic acetylcholine receptors are found primarily in

the the central nervous systemcentral nervous system Functionally the two receptors are also different, Functionally the two receptors are also different, nicotinic nicotinic

AChRsAChRs are are ligand-gated ionligand-gated ion channels while channels while muscarinicmuscarinic AChRs are part of a larger class of AChRs are part of a larger class of G-protein coupled G-protein coupled receptorsreceptors. This larger class utilizes the full-power of the . This larger class utilizes the full-power of the intracellular secondary messenger system which involves intracellular secondary messenger system which involves an increase of intracellular Ca2+ .an increase of intracellular Ca2+ .

Nicotinic Acetylcholine Receptors (nAChRNicotinic Acetylcholine Receptors (nAChR

Binding by two molecules of acetylcholine to the nicotinic Binding by two molecules of acetylcholine to the nicotinic AChR causes a conformational change resulting in the AChR causes a conformational change resulting in the formation of an ion pore.formation of an ion pore.

This produces a rapid increase in cellular permeability of This produces a rapid increase in cellular permeability of Na+ and Ca2+ ions, depolarization and excitation, resulting Na+ and Ca2+ ions, depolarization and excitation, resulting in muscular contraction. Receptor subunits are either alpha in muscular contraction. Receptor subunits are either alpha (alpha2 - alpha9) or beta (beta2 - beta5) types, which leads (alpha2 - alpha9) or beta (beta2 - beta5) types, which leads to quite a number of potential combinations but the alpha-to quite a number of potential combinations but the alpha-subunit is always present in two identical copies as these subunit is always present in two identical copies as these are the sites to which acetylcholine binds. The alpha-are the sites to which acetylcholine binds. The alpha-subunits also determine the binding sites through subunits also determine the binding sites through interaction with the other subunits. Neurotoxins targeting interaction with the other subunits. Neurotoxins targeting this site this site reversibly reversibly block the opening and prevent block the opening and prevent acetylcholine from forming a pore and allowing cations to acetylcholine from forming a pore and allowing cations to pass through.pass through.

Muscarinic Acetylcholine ReceptorsMuscarinic Acetylcholine Receptors

Muscarinic receptors are found in the central Muscarinic receptors are found in the central nervous system synapses rather than at the nervous system synapses rather than at the neuromuscular junction. Muscarinic receptors are neuromuscular junction. Muscarinic receptors are involved in a large number of physiological involved in a large number of physiological functions including heart rate and force, functions including heart rate and force, contraction of smooth muscles and the release of contraction of smooth muscles and the release of neurotransmitters. Molecular cloning has neurotransmitters. Molecular cloning has determined five subtypes of muscarinic receptors, determined five subtypes of muscarinic receptors, based on pharmacological activity they have based on pharmacological activity they have been broken up into M1-M5. All five subtypes are been broken up into M1-M5. All five subtypes are found in the central nervous system while M1-M4 found in the central nervous system while M1-M4 are also scattered widely through a myriad of are also scattered widely through a myriad of tissuestissues

Binding of neurotoxin to Binding of neurotoxin to acetylcholineacetylcholine

Comparison of the muscarinic and nicotinic Comparison of the muscarinic and nicotinic acetylcholine receptors and the effect of acetylcholine receptors and the effect of binding by venom molecules. Ligands for binding by venom molecules. Ligands for nicotinic acetylcholine receptors convert the nicotinic acetylcholine receptors convert the receptor into an ion channel, allowing the receptor into an ion channel, allowing the rapid influx of sodium and calcium ions, upon rapid influx of sodium and calcium ions, upon which the ligand disassociates from the which the ligand disassociates from the receptor. Ligands for muscarinic receptors receptor. Ligands for muscarinic receptors trigger activation of an intracellular enzyme trigger activation of an intracellular enzyme by GTP with this enzyme being subsequently by GTP with this enzyme being subsequently responsible for initiating an intracellular responsible for initiating an intracellular cascade leading to an increase in Ca2+. The cascade leading to an increase in Ca2+. The ligand subsequently disassociates from the ligand subsequently disassociates from the receptor. Venom molecules receptor. Venom molecules reversibly bind to reversibly bind to the nicotinic receptors,the nicotinic receptors, preventing the preventing the binding of acetylcholine to receptor. Venom binding of acetylcholine to receptor. Venom molecules molecules irreversibly bind to the muscarinic irreversibly bind to the muscarinic receptorreceptor, continually stimulating the receptor, continually stimulating the receptor

Basic structure of the neuromuscular junction showing the major channels and Basic structure of the neuromuscular junction showing the major channels and structures involved in nerve transmission. At rest (top), the cytoplasm of the structures involved in nerve transmission. At rest (top), the cytoplasm of the nerve has a net negative charge relative to the outside environment. When nerve has a net negative charge relative to the outside environment. When discharged (bottom), the nerve slightly over-shoots resulting in a slight net discharged (bottom), the nerve slightly over-shoots resulting in a slight net

positive charge.positive charge.  

Sites of action by major classes of animal venom Sites of action by major classes of animal venom

neurotoxinsneurotoxins..

Neurotoxins in snake venom can block transmission of Neurotoxins in snake venom can block transmission of acetylcholine from nerve to muscle at the side of the nerve acetylcholine from nerve to muscle at the side of the nerve ending (pre-synaptic literally,ending (pre-synaptic literally, before the synapse before the synapse), or affect ), or affect the activity of the muscle fiber past the synapse (post-the activity of the muscle fiber past the synapse (post-synaptic literallysynaptic literally after the synapse after the synapse). Most commonly, the ). Most commonly, the postsynaptic method of producing paralysis is an anti-postsynaptic method of producing paralysis is an anti-cholinesterase toxin in venom that prevents cholinesterase toxin in venom that prevents acetylcholinesterase from degrading the acetylcholine.. [8]. acetylcholinesterase from degrading the acetylcholine.. [8].

Presynaptic neurotoxins are commonly called Presynaptic neurotoxins are commonly called ß-neurotoxins ß-neurotoxins and have been isolated from venoms of snakes of families and have been isolated from venoms of snakes of families Elapidae and Viperidae.Elapidae and Viperidae.

ß-bungarotoxinß-bungarotoxin has a phospholipase subunit and a K+ has a phospholipase subunit and a K+ channel binding subunit, and their combined effects are to channel binding subunit, and their combined effects are to destroy sensory and motor neurons [9] destroy sensory and motor neurons [9]

The banded krait venom also contains The banded krait venom also contains alpha-bungarotoxin,alpha-bungarotoxin, which binds to nicotinic acetylcholine receptors, thus which binds to nicotinic acetylcholine receptors, thus preventing acetylcholine from doing so (i.e. it is a receptor preventing acetylcholine from doing so (i.e. it is a receptor antagonist), antagonist), and,kappa bungarotoxinand,kappa bungarotoxin which is an antagonist which is an antagonist of neuronal acetylcholine receptors.[10] of neuronal acetylcholine receptors.[10]

NEUROTOXIN SYSTEMIC S&SNEUROTOXIN SYSTEMIC S&S Neuromuscular junction blockadeNeuromuscular junction blockade ––Muscle paralysis which started from the Muscle paralysis which started from the

group ofgroup of small sized muscles, larger and then small sized muscles, larger and then

generalizedgeneralized ParalysisParalysis ptosisptosis ––droolingdrooling ––dysphagia --> aspirationdysphagia --> aspiration ––respiratory paralysisrespiratory paralysis ––generalized paralysisgeneralized paralysis double vision (double vision (diplopiadiplopia),),

sweatingsweating,,excessive salivation,excessive salivation,a decrease in reflexes, a decrease in reflexes,

It takes about It takes about 10 minutes10 minutes for the for the venomvenom to to affect the nervous system. affect the nervous system.

Mucular weakness sets in Mucular weakness sets in 1 hr1 hr ,lasts upto ,lasts upto 10 10 daysdays

Neurotoxic symptoms usually resolve in Neurotoxic symptoms usually resolve in 2-3 2-3 days. days.

Bilateral ptosis in elapid venom Bilateral ptosis in elapid venom poisoning poisoning

First AidFirst Aid Keep the person calm, reassuring them that bites can be effectively treated in an emergency room. Restrict Keep the person calm, reassuring them that bites can be effectively treated in an emergency room. Restrict movement, and keep the affected area below heart level to reduce the flow of venom.movement, and keep the affected area below heart level to reduce the flow of venom... Remove any rings or constricting items because the affected area may swell. Create a loose splint to help restrict Remove any rings or constricting items because the affected area may swell. Create a loose splint to help restrict

movement of the area.movement of the area.

If the area of the bite begins to swell and change color, the snake was probably poisonous.If the area of the bite begins to swell and change color, the snake was probably poisonous.

Monitor the person's Monitor the person's vital signsvital signs -- temperature, -- temperature, pulsepulse, rate of breathing, and , rate of breathing, and blood pressureblood pressure -- if possible. If there are -- if possible. If there are signs of shock (such as paleness), lay the person flat, raise the feet about a foot, and cover the person with a blanket.signs of shock (such as paleness), lay the person flat, raise the feet about a foot, and cover the person with a blanket.

Get medical help right away.Get medical help right away.

. Bring in the dead snake only if this can be done safely. Do not waste time hunting for the snake, and do not risk . Bring in the dead snake only if this can be done safely. Do not waste time hunting for the snake, and do not risk another bite if it is not easy to kill the snake. Be careful of the head when transporting it -- a snake can actually bite for another bite if it is not easy to kill the snake. Be careful of the head when transporting it -- a snake can actually bite for up to an hour after it's dead (from a reflex).up to an hour after it's dead (from a reflex).

DO NOTDO NOT allow the person to become over-exerted. If necessary, carry the person to safety. allow the person to become over-exerted. If necessary, carry the person to safety. apply a tourniquet. apply a tourniquet. apply cold compresses to a snake bite. apply cold compresses to a snake bite. cut into a snake bite with a knife or razor. cut into a snake bite with a knife or razor. try to suck out the venom by mouth. try to suck out the venom by mouth. give the person stimulants or pain medications unless a doctor tells you to do so. give the person stimulants or pain medications unless a doctor tells you to do so. give the person anything by mouth. give the person anything by mouth. raise the site of the bite above the level of the person's heart. raise the site of the bite above the level of the person's heart.

MANAGEMENTMANAGEMENT

SPECIFIC TREATMENTSPECIFIC TREATMENT Administration of anti-venom -Administration of anti-venom - Polyvalent anti-snake venom contains antibodies against cobra, common krait and viper. Polyvalent anti-snake venom contains antibodies against cobra, common krait and viper.

5 vials are given if signs are mild -primarily local manifestations.5 vials are given if signs are mild -primarily local manifestations.10 vials if signs are moderate -bleeding from gums, ptosis.10 vials if signs are moderate -bleeding from gums, ptosis.15 vials if signs are severe -vascular collapse, progressive paralysis.15 vials if signs are severe -vascular collapse, progressive paralysis.

1/3 of the dose should be given subcutaneously (near bite but not in fingers or toes).1/3 of the dose should be given subcutaneously (near bite but not in fingers or toes).1/3 intramuscularly.1/3 intramuscularly.1/3 intravenously.1/3 intravenously.

The intravenous dose can be repeated every 6 hours till the symptoms disappear. For sea-snake The intravenous dose can be repeated every 6 hours till the symptoms disappear. For sea-snake bites, special antivenoms are available.bites, special antivenoms are available.

More on Anti-Snake Venom and Its AdministrationMore on Anti-Snake Venom and Its Administration Manage toxic signs/symptomsManage toxic signs/symptoms Anti-venom acts only against circulating toxin, not toxin fixed to tissue. Therefore, specific Anti-venom acts only against circulating toxin, not toxin fixed to tissue. Therefore, specific

measures have to be taken.measures have to be taken.In case of neuro toxic signs and symptoms, atropine (0.6 mg) subcutaneously should be followed by In case of neuro toxic signs and symptoms, atropine (0.6 mg) subcutaneously should be followed by 5 injections of neostigmine (0.5 mg) intravenously (repeated 2 hourly depending on response) to 5 injections of neostigmine (0.5 mg) intravenously (repeated 2 hourly depending on response) to reverse muscle paralysis.reverse muscle paralysis.Take supportive measuresTake supportive measures

These include blood or plasma transfusion to combat shock, These include blood or plasma transfusion to combat shock, mechanical respiration to combat respiratory distress, mechanical respiration to combat respiratory distress, antibiotics to prevent secondary infection. Neuromuscular paralysis is the most dreadful antibiotics to prevent secondary infection. Neuromuscular paralysis is the most dreadful complication of snake bite. It may occur within 15 minutes  but may be delayed for several hours. complication of snake bite. It may occur within 15 minutes  but may be delayed for several hours. To tackle hypersensitivity reactions to antivenom-steroids, adrenaline and antihistamines may be To tackle hypersensitivity reactions to antivenom-steroids, adrenaline and antihistamines may be given. given.

Literatures: Literatures: 1.      Reid, H.A. (1964). Cobra bites. 1.      Reid, H.A. (1964). Cobra bites. Br. Med. J.Br. Med. J. 22, 540-545. , 540-545. 2.      Reid, H.A., Chan, K.E. and Thean, P.C. (1963). Prolonged coagulation defect (defibrination syndrome) in Malayan viper bite.2.      Reid, H.A., Chan, K.E. and Thean, P.C. (1963). Prolonged coagulation defect (defibrination syndrome) in Malayan viper bite. Lancet Lancet, , ii, 621-626. , 621-626. 3.      Reid, H.A., Thean, P.C., Chan, K.E. and Baharom, A.R. (1963). Clinical effects of bites by Malayan viper. 3.      Reid, H.A., Thean, P.C., Chan, K.E. and Baharom, A.R. (1963). Clinical effects of bites by Malayan viper. LancetLancet ii, 617-621. , 617-621. 4.      Reid, H.A. and Lim, K.J. (1957). Sea-snake bite. 4.      Reid, H.A. and Lim, K.J. (1957). Sea-snake bite. Br. Med. J.Br. Med. J. 22, 1266-1272. , 1266-1272. 5.      Reid, H.A., Theakston, R.D.S. (1983) The management of snake bite. 5.      Reid, H.A., Theakston, R.D.S. (1983) The management of snake bite. Bull. W.H.O.Bull. W.H.O., , 6161, 885-895. , 885-895. 6.      Mitrakul, C. (1973). Effects of green pit viper venoms on blood coagulation, platelets and the fibrinolytic enzyme systems: studies in vivo and in 6.      Mitrakul, C. (1973). Effects of green pit viper venoms on blood coagulation, platelets and the fibrinolytic enzyme systems: studies in vivo and in

vitro. vitro. Am. J. clin. PatholAm. J. clin. Pathol. . 6060, 654-662. , 654-662. 7.      Warrell, D.A., Looareesuwan, S., White, N.J., Theakston, R.D.G., Warrell, M.J., Kosakarn, W., and Reid, H.A. (1983). Severe neurotoxic 7.      Warrell, D.A., Looareesuwan, S., White, N.J., Theakston, R.D.G., Warrell, M.J., Kosakarn, W., and Reid, H.A. (1983). Severe neurotoxic

envenoming by the Malayan krait, Bungarus candidus: response to antivenom and anti-cholinesterase. envenoming by the Malayan krait, Bungarus candidus: response to antivenom and anti-cholinesterase. Br. Med. JBr. Med. J. . 286286, 678-689. , 678-689. 8.      Warrell, D.A., Theakston, R.D.G., Phillips, R.E., Chanthavanich, P., Viravan, C., Supanaranond, W., Karbwang, J., Ho, M., Hutton, R.A. and Vejcho, 8.      Warrell, D.A., Theakston, R.D.G., Phillips, R.E., Chanthavanich, P., Viravan, C., Supanaranond, W., Karbwang, J., Ho, M., Hutton, R.A. and Vejcho,

S. (1986). Randomized comparative trial of three monospecific antivenoms for bites by the Malayan pit viper (Calloselasma rhodostoma) in southern S. (1986). Randomized comparative trial of three monospecific antivenoms for bites by the Malayan pit viper (Calloselasma rhodostoma) in southern Thailand: clinical and laboratory correlations. Thailand: clinical and laboratory correlations. Am. J. Trop. Med. HygAm. J. Trop. Med. Hyg. . 3535, 1235-1247. , 1235-1247.

9.      Lim, B.L. (1982) 9.      Lim, B.L. (1982) Poisonous Snakes of Peninsular MalaysiaPoisonous Snakes of Peninsular Malaysia. 2nd Ed. Malayan Nature Society, Kuala Lumpur, 72pp. . 2nd Ed. Malayan Nature Society, Kuala Lumpur, 72pp. 10.  Reid, H.A. (1968) Symptomatology, pathology and treatment of land snake bites in India and Southeast Asia. In: 10.  Reid, H.A. (1968) Symptomatology, pathology and treatment of land snake bites in India and Southeast Asia. In: Venomous Animals and Their Venomous Animals and Their

VenomsVenoms. Vol.1. (Buckely, E.D., Bucheri, W., and Deulofeu, V. Eds.), Academic Press, New York. Pp. 611-642. . Vol.1. (Buckely, E.D., Bucheri, W., and Deulofeu, V. Eds.), Academic Press, New York. Pp. 611-642. 11.  Tan, N.H. (1991) The biochemistry of venoms of some venomous snakes of Malaysia. – A Review11.  Tan, N.H. (1991) The biochemistry of venoms of some venomous snakes of Malaysia. – A Review . Tropical Biomedicine. Tropical Biomedicine 88, 91-103. , 91-103. References References ↑↑ Mackessy SP Mackessy SP et alet al (2003) Ontogenetic variation in venom composition and diet of crotalus oreganus concolor: a case of venom paedomorphosis? (2003) Ontogenetic variation in venom composition and diet of crotalus oreganus concolor: a case of venom paedomorphosis?

CopeiaCopeia 20032003:769–782 DOI: 10.1643/HA03-037.1 :769–782 DOI: 10.1643/HA03-037.1 ↑↑ Mackessya SP Biochemistry and pharmacology of colubrid snake venoms Mackessya SP Biochemistry and pharmacology of colubrid snake venoms ↑↑ Veto T Veto T et alet al (2007) Treatment of the first known case of king cobra envenomation in the UK, complicated by severe anaphylaxis (2007) Treatment of the first known case of king cobra envenomation in the UK, complicated by severe anaphylaxis AnaesthesiaAnaesthesia

6262:75-8 :75-8 ↑↑ Singh G Singh G et alet al (1999) Neuromuscular transmission failure due to common krait (Bungarus caeruleus) envenomation (1999) Neuromuscular transmission failure due to common krait (Bungarus caeruleus) envenomation Muscle & NerveMuscle & Nerve 2222:1637-43 :1637-43 ↑↑ Dart RC Dart RC et alet al (2006) Chapter 195. Reptile Bites. Tintinalli's Emergency Medicine > Section 15: Environmental Injuries. The McGraw-Hill Companies (2006) Chapter 195. Reptile Bites. Tintinalli's Emergency Medicine > Section 15: Environmental Injuries. The McGraw-Hill Companies ↑↑ José María Gutiérrez (2003) Guest editor's foreword to issue of ToxiconJosé María Gutiérrez (2003) Guest editor's foreword to issue of Toxicon 4242:825-6:825-6 ↑↑ Kardong K, Bels V (1998) Rattlesnake strike behavior: Kinematics Kardong K, Bels V (1998) Rattlesnake strike behavior: Kinematics J Exp BiolJ Exp Biol 201201:837–50 :837–50 ↑↑ Lewis RL, Gutmann L (2004) Snake venoms and the neuromuscular junction Lewis RL, Gutmann L (2004) Snake venoms and the neuromuscular junction Seminars in NeurologySeminars in Neurology 24:175-9 24:175-9 PMID 15257514PMID 15257514 ↑↑ Kwong PD Kwong PD et alet al (1995) Structure of ß2-bungarotoxin: potassium channel binding by Kunitz modules and targeted phospholipase action (1995) Structure of ß2-bungarotoxin: potassium channel binding by Kunitz modules and targeted phospholipase action StructureStructure

3:1109-19 3:1109-19 PMID 8590005PMID 8590005 ↑↑ Wolf KM Wolf KM et alet al (1988) kappa-Bungarotoxin: binding of a neuronal nicotinic receptor antagonist to chick optic lobe and skeletal muscle (1988) kappa-Bungarotoxin: binding of a neuronal nicotinic receptor antagonist to chick optic lobe and skeletal muscle Brain ResBrain Res

439:249-58 439:249-58 PMID 3359187PMID 3359187 ↑↑ Asher O Asher O et alet al (1998) How does the mongoose cope with alpha-bungarotoxin? Analysis of the mongoose muscle AChR alpha-subunit (1998) How does the mongoose cope with alpha-bungarotoxin? Analysis of the mongoose muscle AChR alpha-subunit Ann N Y Acad Ann N Y Acad

SciSci 841:97-100, 841:97-100, PMID 9668225PMID 9668225 ↑↑ Trinh KX Trinh KX et alet al (2005) The production of (2005) The production of Bungarus candidusBungarus candidus antivenom from horses immunized with venom and its application for the treatment Of antivenom from horses immunized with venom and its application for the treatment Of

snake bite patients in Vietnam: 75 snake bite patients in Vietnam: 75 Therapeutic Drug MonitoringTherapeutic Drug Monitoring 27:230 27:230 ↑↑ Auerbach PS, Norris RL (2006):Chapter 378. Disorders Caused by Reptile Bites and Marine Animal Exposures. in Harrison's Internal Medicine. Auerbach PS, Norris RL (2006):Chapter 378. Disorders Caused by Reptile Bites and Marine Animal Exposures. in Harrison's Internal Medicine. ↑↑ Schneemann M Schneemann M et alet al (2004) Life-threatening envenoming by the Saharan horned viper ( (2004) Life-threatening envenoming by the Saharan horned viper (CerastesCerastes cerastescerastes) causing micro-angiopathic haemolysis, ) causing micro-angiopathic haemolysis,

coagulopathy and acute renal failure: clinical cases and review. coagulopathy and acute renal failure: clinical cases and review. QjmQjm 9797:717-27, :717-27, PMID 15496528PMID 15496528

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