Snake venom toxicity: - PowerPoint Presentation

Slide1

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.

Slide9
Slide10

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