Transcript Snake venom toxicity: usefulness and limitations of antivenom

Snake venom toxicity: Usefulness
and limitations of antivenom
Dr Aniruddha Ghose
Chittagong Medical College
Overview
• Composition of snake
venom
• Actions of components
• Phenotypic expressions
• Actions of anti venom
• Limitations of anti
venom
• Clinical implication
Snake venom: composition
• Snake venoms are the most complex of all natural
venoms and poisons
– mixture of more than 100 different components
• Mostly protein
– enzymes, polypeptide toxins and non-toxic proteins
• Non protein components
– carbohydrates, metals, lipids, free amino acids,
nucleosides and biogenic amines (serotonin and
acetylcholine)
• Evolutionary pressures have selected venom
toxins that are specific for many targets in
animal tissues
• The toxins of most importance in human
envenoming include those that affect the
nervous, cardiovascular, and haemostatic
systems, and cause tissue necrosis
Venom enzymes
• These include digestive hydrolases,
hyaluronidase, kininogenase.
• Most venoms contain l-amino acid oxidase,
phosphomono- and diesterases, 5’-nucleotidase,
DNAase, NAD-nucleosidase, phospholipase A2
and peptidases.
• Zinc metalloproteinase haemorrhagins: Damage
vascular endothelium, causing bleeding
• Serine proteases and other procoagulant
enzymes
Venom enzymes
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Phospholipase A2 (lecithinase)
Acetylcholinesterase
Hyaluronidase
Proteolytic enzymes (metalloproteinases,
endopeptidases or hydrolases) and polypetide
cytotoxins (“cardiotoxins”)
Samson A.O., Scherf. T., Eisenstein M., Chill J., and Anglister J., “The mechanism for acetylcholine receptor inhibition by alphaneurotoxins and species-specific resistance to alpha-bungarotoxin revealed by NMR” , 2002, Neuron, 35, 319-332.
Neurotoxicity
Neuromuscular junction showing ion channels and sites of action of presynaptic and postsynaptic
snake venom neurotoxins, and three neurotoxins specifi c to mamba (Dendroaspis) venoms—ie, dendrotoxins,
fasciculins, and calciseptine
Venom polypeptide toxins
(“neurotoxins”)
• Postsynaptic (α) neurotoxins: α-bungarotoxin
and cobrotoxin: bind to acetylcholine receptors
at the motor endplate.
• Presynaptic (β) neurotoxins: β-bungarotoxin,
crotoxin, and taipoxin, contain a phospholipase
A subunit
– These release acetylcholine at the nerve endings at
neuromuscular junctions and then damage the
endings, preventing further release of transmitter
Samson A.O., Scherf. T., Eisenstein M., Chill J., and Anglister J., “The mechanism for acetylcholine receptor inhibition by alphaneurotoxins and species-specific resistance to alpha-bungarotoxin revealed by NMR” , 2002, Neuron, 35, 319-332.
Synaptic vesicles labelled
with
anti-synaptophysin IgG
(green)
Acth receptors labelled
with TRITC-conjugated abungarotoxin (red).
Combined images
Faiz et al. Brain 2010: 133; 3181–3193
Neurotoxicity
• Neurotoxins bind to their receptors with high
affinity, making reversal of paralysis by antivenom
implausible.
• Rapid improvement in neurotoxicity has been
noted when postsynaptic toxins were
implicated—eg, Asian cobras and Australasian
death adders (Acanthophis spp).
• Anticholinesterases sometimes reverse
postsynaptic neurotoxicity in envenomed
patients.
Naja kaouthia bite:
neurotoxic effects
Naja kaouthia bite:
neurotoxic effects
• Paralysis in envenomed people starts with
ptosis, external ophthalmoplegia, and
mydriasis, descending to involve muscles
innervated by the other cranial and spinal
nerves and leading to bulbar and respiratory
paralysis and, if ventilation is supported,
eventually to total flaccid paralysis
Necrotoxicity
• A range of venom myotoxic and cytolytic factors
– zinc-dependent metalloproteinases and myotoxic
phospholipases A2.
• Digestive hydrolases, hyaluronidase, polypeptide
cytotoxins (Elapidae)
• Secondary effects of inflammation
• Ischaemia, resulting from thrombosis,
intracompartmental syndrome, or application of
a tight tourniquet, contributes to tissue loss.
Naja kaouthia bite:
local necrosis
© DA Warrell
Myotoxicity
• Myotoxic phospholipases A2 in venoms of
some species of Viperidae and Elapidae,
especially sea snakes, cause generalised
rhabdomyolysis that is often complicated by
acute renal failure (B Niger)
Haemotoxicity
• Serine proteases, metalloproteinases, C-type
lectins, disintegrins, and phospholipases: by
activating or inhibiting coagulant factors or
platelets, and disrupting vascular endothelium.
• Viperidae contain thrombinlike fibrinogenases
and activators of prothrombin, factors V, X, and
XIII, and endogenous plasminogen.
Haemotoxicity
• Toxins bind to a range of platelet receptors,
inducing or inhibiting aggregation.
• Phospholipases A2 hydrolyse or bind to
procoagulant phospholipids and inhibit the
prothrombinase complex.
• Haemorrhagins (metalloproteinases) damage
vascular endothelium: Spontaneous systemic
bleeding
Haemotoxicity
• The combination of consumption coagulopathy,
anticoagulant activity, impaired and few
platelets, and vessel wall damage can result in
severe bleeding, a common cause of death after
bites by Viperidae, Australian Elapidae, and
some Colubridae.
Cryptelytrops erythrusus
Cadiotoxicity
• Hypotension after snake bite
– permeability factors that cause hypovolaemia
from extravasation of plasma
– toxins acting directly or indirectly on cardiac
muscle, vascular smooth muscle, and on other
tissues.
• Sarafotoxins potently vasoconstrict coronary
and other arteries, and delay atrioventricular
conduction
Clinical effects of venom action
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Neurotoxicity
Myotoxicity
Haemotoxicity
Necrotoxicity
• Cardiotoxicity
Role of antivenom
• The only specific antidote to the toxins in
snake venom
• Hyperimmune globulin from an animal that
has been immunised with the appropriate
venom
• Albert Calmette: “Serum antivenimeuse”:
1895: quickly accepted
• Immunoglobulin antivenoms are accepted as
essential drugs
• Reappraisal is needed
• The limitations of antivenom treatment
should be recognized
Limitations of Anti Venom
• Patients with respiratory, circulatory, and renal
failure need urgent resuscitation as well as
antivenom.
Role of AV in neurotoxicity
• Pre synaptic neuro toxicity: can not be
reversed especially in Krait bite
• Entubation is essential
– Respiaratory failure
– Impending resp failure
• Neostigmine: no effect
• Post-synaptic paralysis: (clinical evidence
confirming experimental studies) indicating AV
can reverse this paralysis in at least some
cases.
– Naja kaouthia
Low-cost, rechargeable,
portable, disposable ventilator
$300: typical ventilators
$8,000-$60,000
SOP should be
• First ensure adequate respiratory effort
– Entubation
– Amboo
• Neostigmine
• Antivenom
• Simultaneous approach
Role of AV in reversing coagulopathy
• Controversial
– for most species there is good clinical evidence AV
can help control or reverse coagulopathy
• The caveat is that if it is a consumptive
coagulopathy the response time will be longer
– While AV can neutralize venom, it cannot speed
replacement of consumed coagulation factors or
fibrinogen
Role of AV in reversing coagulopathy
• Controversial
– for most species there is good clinical evidence AV
can help control or reverse coagulopathy
• The caveat is that if it is a consumptive
coagulopathy the response time will be longer
– While AV can neutralize venom, it cannot speed
replacement of consumed coagulation factors or
fibrinogen
No anti venom for Pit vipers
Role of AV in myolysis
• Also uncertain
• Theoretically it could be argued it won't help
much if major myolysis is already established.
• Clinical experience shows cases where use of
AV was associated with a marked improvement
in both symptoms and CK levels within a short
time (a few hours only).
Role of AV in local tissue necrosis
• Treating local tissue injury: difficult
• Evidence for using AV is muddy
• Probably helps to at least some extent,
particularly if given early
Local tissue destruction
Venom injection
In situ injection of
toxin inhibitors or
antibody fragments
iv administration of
antivenom
Stimulus for tissue
regeneration
Tissue repair and
regeneration

Local
effects
Necrosis
Hemorrhage
ECM degradation
© José María Gutiérrez
Inflammatory reaction
to envenomation
Ancillary
interventions

Further tissue
damage
Blockade of deleterious
effects of inflammation
Role of AV in Nephrotoxicity
• Possible causes:
– Hypotension
– DIC
– Direct nephrotoxic action
• AV even given early failed to prevent
development of renal failure (Myanmar)
Treating renal failure
AV hypersensitivity
• Dependent on the dose, route, and speed of
administration, and the quality of refinement,
the risk of any early reaction varies from
about 3% to more than 80%
• Only about 5–10% of reactions are associated
with severe symptoms such as bronchospasm,
angiooedema, or hypotension
• May be life threatening
• Treating physicians should actively look for
early features like restlessness, urticaria
• Prompt intervention
• React at the first sign e,g, single urticaria
– Adrenalin, steroid, H1 blocker: Repeat as necessary
• “Pre medication”!!!
So
• Don’t be disappointed if you don’t have anti
venom
• Don’t be content when you have it
• Remain vigilant
Conclusion
• Snake venom is a complex mixture of different
component
• Phenotypic presentation depends on action of
these compounds on victims body
• Anti venom is the mainstay of treatment
• Anti venom can not neutralize all effects of
venom
• Supportive treatment is crucial
• Attending physician has an important role in
determining outcome
Acknowledgement
• Prof David A Warrell
• Prof Jullian White
Thank You