Snake bites from neurotoxic snakes can cause paralysis and respiratory failure through the venom's effects on acetylcholine receptors at neuromuscular junctions. The main neurotoxins in elapid snakes (cobras and kraits) are postsynaptic neurotoxins, cardiotoxins, and phospholipases A, which bind irreversibly to nicotinic acetylcholine receptors, blocking the receptor and preventing muscle contraction. Treatment involves administration of polyvalent antivenom, atropine and neostigmine to reverse paralysis, supportive care, and management of symptoms like respiratory distress. Prompt medical treatment is important to prevent paralysis, respiratory failure, and other toxic effects of the venom on acetylcholine receptors and the

1. SNAKE BITE

2. • Neurotoxin producing snakes
 Elapinae: represented by the five genera Naja,
Bungarus, Ophiophagus, Maticora and Calliophis
 Banded krait (Bungarus fasciatus)
 – Malayan krait (Bungarus candidus)
 – Red-headed krait (Bungarus flaviceps)
 Mojave rattlesnake
 Coral snakes

3. venom
 The main toxins in the venoms of elapid
snakes (cobras, kraits and sea snakes)
include:
1. polypeptide postsynaptic neurotoxins,
2. cardiotoxins and
3. phospholipases A

4. MECHANISM OF ACTION
 It takes about 10 minutes for the venom to affect the
nervous system.
 Most neurotoxins in snake venoms are too large to cross the
blood-brain barrier, and so they usually exert their effects on
the peripheral nervous system rather than directly on the
brain and spinal cord.
 The neurotoxic effects are mainly at the postsynaptic level of
the neuromuscular junction where the neurotoxins block acetylcholine
receptors, thereby producing muscular paralysis and
respiratory failure

5. Acetylcholine Receptors
Acetylcholine has two modes of action,
 a nicotine-like (nicotinic) or
 a muscarine-like (muscarinic) action,
with the former blocked by curare and
the later by atropine.
 Nicotinic acetylcholine receptors are found primarily at neuromuscular
junctions while
 muscarinic acetylcholine receptors are found primarily in the central
nervous system
 Functionally the two receptors are also different, nicotinic AChRs are
ligand-gated ion channels while muscarinic AChRs are part of a larger
class of G-protein coupled receptors. This larger class utilizes the full-
power of the intracellular secondary messenger system which
involves an increase of intracellular Ca2+ .


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

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

8. Binding of neurotoxin to
acetylcholine

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

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

11. Sites of action by major classes of animal venom
neurotoxins.

12.  Neurotoxins in snake venom can block transmission of acetylcholine
from nerve to muscle at the side of the nerve ending (pre-synaptic
literally, before the synapse), or affect the activity of the muscle fiber
past the synapse (post-synaptic literally after the synapse). Most
commonly, the postsynaptic method of producing paralysis is an
anti-cholinesterase toxin in venom that prevents
acetylcholinesterase from degrading the acetylcholine.. [8].
 Presynaptic neurotoxins are commonly called ß-neurotoxins and
have been isolated from venoms of snakes of families Elapidae and
Viperidae.
 ß-bungarotoxin has a phospholipase subunit and a K+ channel binding
subunit, and their combined effects are to destroy sensory and
motor neurons [9]
 The banded krait venom also contains alpha-bungarotoxin, which binds
to nicotinic acetylcholine receptors, thus preventing acetylcholine
from doing so (i.e. it is a receptor antagonist), and,kappa bungarotoxin
which is an antagonist of neuronal acetylcholine receptors.[10]

13. NEUROTOXIN SYSTEMIC S&S
 Neuromuscular junction blockade
 –Muscle paralysis which started from the group of
 small sized muscles, larger and then generalized
 Paralysis
 ptosis
 –drooling
 –dysphagia --> aspiration
 –respiratory paralysis
 –generalized paralysis
 double vision (diplopia),
sweating,
excessive salivation,
a decrease in reflexes,
 It takes about 10 minutes for the venom to affect the
nervous system.
 Mucular weakness sets in 1 hr ,lasts upto 10 days
 Neurotoxic symptoms usually resolve in 2-3 days.

14. Bilateral ptosis in elapid venom
poisoning

15. MANAGEMENT
 First Aid
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.
.
Remove any rings or constricting items because the affected area may swell. Create a loose splint to help restrict movement of the area.
 If the area of the bite begins to swell and change color, the snake was probably poisonous.
 Monitor the person's vital signs -- temperature, pulse, rate of breathing, and blood pressure -- if possible. If there are signs of shock (such
pulse,
as paleness), lay the person flat, raise the feet about a foot, and cover the person with a blanket.
 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 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).
 DO NOT
 allow the person to become over-exerted. If necessary, carry the person to safety.
 apply a tourniquet.
apply cold compresses to a snake bite.
 cut into a snake bite with a knife or razor.
 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 anything by mouth.
 raise the site of the bite above the level of the person's heart.

16. SPECIFIC TREATMENT
 Administration of anti-venom -
 Polyvalent anti-snake venom contains antibodies against cobra, common krait and viper.
5 vials are given if signs are mild -primarily local manifestations.
10 vials if signs are moderate -bleeding from gums, ptosis.
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 intramuscularly.
1/3 intravenously.
 The intravenous dose can be repeated every 6 hours till the symptoms disappear. For sea-snake bites, special
antivenoms are available.
 More on Anti-Snake Venom and Its Administration
 Manage toxic signs/symptoms
 Anti-venom acts only against circulating toxin, not toxin fixed to tissue. Therefore, specific measures have to be
taken.
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 reverse muscle paralysis.
Take supportive measures
 These include blood or plasma transfusion to combat shock,
mechanical respiration to combat respiratory distress,
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.
To tackle hypersensitivity reactions to antivenom-steroids, adrenaline and antihistamines may be given.

17.  Li teratures:
 1. Reid, H.A. (1964). Cobra bites. Br. Med. J. 2 , 540-545.
 2. Reid, H.A., Chan, K.E. and Thean, P.C. (1963). Prolonged coagulation defect (defibrination syndrome) in Malayan viper bite. Lancet, i , 621-626.
 3. Reid, H.A., Thean, P.C., Chan, K.E. and Baharom, A.R. (1963). Clinical effects of bites by Malayan viper. Lancet i , 617-621.
 4. Reid, H.A. and Lim, K.J. (1957). Sea-snake bite. Br. Med. J. 2 , 1266-1272.
 5. Reid, H.A., Theakston, R.D.S. (1983) The management of snake bite. Bull. W.H.O., 61 , 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 vitro. Am. J. clin.
Pathol. 60 , 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 envenoming by the
Malayan krait, Bungarus candidus: response to antivenom and anti-cholinesterase. Br. Med. J. 286 , 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, 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. Am. J. Trop. Med. Hyg. 35 , 1235-1247.
 9. Lim, B.L. (1982) Poisonous Snakes of Peninsular Malaysia. 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: Venomous Animals and Their Venoms. 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 Review. Tropical Biomedicine 8 , 91-103.
 References
 ↑ Mackessy SP et al (2003) Ontogenetic variation in venom composition and diet of crotalus oreganus concolor: a case of venom paedomorphosis? Copeia 2003 :769–
782 DOI: 10.1643/HA03-037.1
 ↑ Mackessya SP Biochemistry and pharmacology of colubrid snake venoms
 ↑ Veto T et al (2007) Treatment of the first known case of king cobra envenomation in the UK, complicated by severe anaphylaxis Anaesthesia 62 :75-8
 ↑ Singh G et al (1999) Neuromuscular transmission failure due to common krait (Bungarus caeruleus) envenomation Muscle & Nerve 22 :1637-43
 ↑ Dart RC et al (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 Toxicon 42 :825-6
 ↑ Kardong K, Bels V (1998) Rattlesnake strike behavior: Kinematics J Exp Biol 201 :837–50
 ↑ Lewis RL, Gutmann L (2004) Snake venoms and the neuromuscular junction Seminars in Neurology 24:175-9 PMID 15257514
 ↑ Kwong PD et al (1995) Structure of ß2-bungarotoxin: potassium channel binding by Kunitz modules and targeted phospholipase action Structure 3:1109-19
PMID 8590005
 ↑ Wolf KM et al (1988) kappa-Bungarotoxin: binding of a neuronal nicotinic receptor antagonist to chick optic lobe and skeletal muscle Brain Res 439:249-58
PMID 3359187
 ↑ Asher O et al (1998) How does the mongoose cope with alpha-bungarotoxin? Analysis of the mongoose muscle AChR alpha-subunit Ann N Y Acad Sci 841:97-100,
PMID 9668225
 ↑ Trinh KX et al (2005) The production of Bungarus candidus antivenom from horses immunized with venom and its application for the treatment Of snake bite patients in
Vietnam: 75 Therapeutic Drug Monitoring 27:230
 ↑ Auerbach PS, Norris RL (2006):Chapter 378. Disorders Caused by Reptile Bites and Marine Animal Exposures. in Harrison's Internal Medicine.
 ↑ Schneemann M et al (2004) Life-threatening envenoming by the Saharan horned viper (Cerastes cerastes) causing micro-angiopathic haemolysis, coagulopathy and
acute renal failure: clinical cases and review. Qjm 97 :717-27, PMID 15496528

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