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 ID: 437791
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Snake venom toxicity: Usefulness and limitations of antivenom
Dr
Aniruddha
Ghose
Chittagong
Medical CollegeSlide2
Overview
Composition of snake venom
Actions of components
Phenotypic expressionsActions of anti venomLimitations of anti venomClinical implicationSlide3
Snake venom: composition
Snake venoms are the most complex of all
natural venoms
and poisonsmixture
of more than 100 different
components
M
ostly proteinenzymes, polypeptide toxins and non-toxic proteinsNon protein componentscarbohydrates, metals, lipids, free amino acids, nucleosides and biogenic amines (serotonin and acetylcholine) Slide4
Evolutionary pressures have selected venom toxins
that are specific
for many targets
in animal tissuesThe toxins of most importance in human envenoming include
those that
affect
the nervous, cardiovascular,
and haemostatic systems, and cause tissue necrosisSlide5
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 bleedingSerine
proteases and other
procoagulant
enzymes Slide6
Venom enzymes
Phospholipase A2 (
lecithinase
)AcetylcholinesteraseHyaluronidaseProteolytic 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 alpha-neurotoxins and species-specific resistance to alpha-
bungarotoxin
revealed by NMR” , 2002, Neuron, 35, 319-332.
Slide7
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 calciseptineSlide8
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 alpha-neurotoxins and species-specific resistance to alpha-
bungarotoxin
revealed by NMR” , 2002, Neuron, 35, 319-332.
Slide9Slide10
Faiz et al. Brain 2010: 133; 3181–3193
Synaptic vesicles
labelled
with
anti-
synaptophysin
IgG
(green)
Acth
receptors
labelled
with TRITC-conjugated a-
bungarotoxin
(red).
Combined imagesSlide11
Neurotoxicity
N
eurotoxins
bind to their receptors with high affinity, making reversal of paralysis by antivenom implausible. R
apid
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
. Slide12
Naja kaouthia
bite:
neurotoxic effectsSlide13
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 paralysisSlide14
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.Slide15
Naja kaouthia
bite: local necrosis
© DA
WarrellSlide16
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)Slide17
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
. Slide18
HaemotoxicityToxins bind to a range of platelet receptors, inducing or inhibiting aggregation.
P
hospholipases
A2 hydrolyse or bind to procoagulant phospholipids and inhibit the prothrombinase
complex
.
H
aemorrhagins (metalloproteinases) damage vascular endothelium: Spontaneous systemic bleedingSlide19
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. Slide20
Cryptelytrops
erythrususSlide21
Cadiotoxicity
Hypotension after snake bite
permeability
factors that cause hypovolaemia from extravasation of plasmatoxins
acting directly or indirectly on cardiac muscle
, vascular
smooth muscle, and on other tissues.
Sarafotoxins potently vasoconstrict coronary and other arteries, and delay atrioventricular conductionSlide22
Clinical effects of venom action
Neurotoxicity
Myotoxicity
HaemotoxicityNecrotoxicityCardiotoxicitySlide23
Role of antivenom
The
only
specific antidote to the toxins in snake venomHyperimmune globulin from an animal that has
been
immunised
with the appropriate venom Albert Calmette: “Serum antivenimeuse”: 1895: quickly acceptedSlide24
Immunoglobulin antivenoms
are accepted as
essential drugs
Reappraisal is neededThe limitations of antivenom treatment should be
recognizedSlide25
Limitations of Anti VenomPatients with respiratory, circulatory, and renal failure need urgent resuscitation as well as
antivenom
.Slide26
Role of AV in neurotoxicity
Pre synaptic
neuro
toxicity: can not be reversed especially in Krait biteEntubation is essentialRespiaratory failureImpending resp
failure
Neostigmine: no effectSlide27
Low-cost, rechargeable, portable, disposable ventilator
$300: typical ventilators $8,000-$60,000
P
ost
-synaptic
paralysis:
(
clinical
evidence confirming experimental
studies)
indicating AV can reverse this paralysis in at least some cases.
Naja
kaouthia
Slide28
SOP should beFirst ensure adequate respiratory effort
Entubation
A
mbooNeostigmineAntivenom
Simultaneous approachSlide29
Role of AV in reversing coagulopathy
Controversial
for
most species there is good clinical evidence AV can help control or reverse coagulopathyThe caveat is that if it is a consumptive coagulopathy the response time will be longer
W
hile
AV can
neutralize venom, it cannot speed replacement of consumed coagulation factors or fibrinogen Slide30
Role of AV in reversing coagulopathy
Controversial
for
most species there is good clinical evidence AV can help control or reverse coagulopathyThe caveat is that if it is a consumptive coagulopathy the response time will be longer
W
hile
AV can
neutralize venom, it cannot speed replacement of consumed coagulation factors or fibrinogen No anti venom for Pit vipersSlide31
Role of AV in myolysis
A
lso 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). Slide32
Role of AV in local tissue necrosis
Treating local tissue
injury: difficult
Evidence for using AV is muddyProbably helps to at least some extent, particularly if given earlySlide33
Venom injection
Inflammatory reaction
to envenomation
Further tissue
damage
In situ
injection of
toxin inhibitors or
antibody fragments
iv administration of
antivenom
Necrosis
Hemorrhage
ECM degradation
Blockade of deleterious
effects of inflammation
Tissue repair and
regeneration
Stimulus for tissue
regeneration
Ancillary
interventions
Local
effects
Local tissue destruction
© José María GutiérrezSlide34
Role of AV in Nephrotoxicity
Possible causes:
Hypotension
DICDirect nephrotoxic actionAV even given early failed to prevent development of renal failure (Myanmar)Slide35
Treating
renal
failureSlide36
AV hypersensitivityDependent 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 hypotensionMay be life threateningSlide37
Treating physicians should actively look for early features like restlessness,
urticaria
Prompt intervention
React
at the first sign
e,g
, single
urticariaAdrenalin, steroid, H1 blocker: Repeat as necessary
“Pre medication”!!!Slide38
SoDon
’
t be disappointed if you don
’t have anti venomDon’t be content when you have itRemain vigilantSlide39
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 venomSupportive treatment is crucialAttending physician has an important role in determining outcomeSlide40
AcknowledgementProf David A
Warrell
Prof
Jullian WhiteSlide41
Thank You