Menge T. B.

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UPDATES ON VACCINESANTISNAKE VENOM

• Menge T. B.
• B. Pharm M.Sc (Pharmacology Toxicology)

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EPIDEMIOLOGY

• There are about 3000 species of snakes worldwide
• About 300 are of medical significance (i.e.
  venomous).
• Africa
• 400 snake species
• most are relatively harmless.
• Approximately 100 species are medically important
  
• 30 species have been known to cause death.

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EPIDEMIOLOGY

• It has been estimated that about 1,000,000 snake
  bites occur annually around the world, 40,000 of
  which result in deaths.
• In Africa 400-1000
• Nigeria, recent statistics show that 80 of all
  hospital admissions in some districts are due to
  snake bites,
• South Africa, 30-80 hospital admissions per
  100,000 persons are due to snake bites.
• In India 30,000 deaths occur annually due to
  snake bites.
• Malindi District Hospital records.  Jan. 2007 -
  Aug. 2008
• Total No. of cases 76
• Treated with antivenom 21 (but query on 3
  cases)
• Fatalities 1

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Bioken, Watamu, Kenya Nov. 1997 - Nov. 2007
Species Species
Dangerous Puff adders 33 (2 fatal)
Dangerous Cobras 17 (3 fatal)
Dangerous Black mamba 5 (2 fatal)
Dangerous Green mamba 6
Dangerous Boomslang 2 (1 fatal)
Dangerous Twig snake 1
Venom in eyes 11
Non - lethal Mole vipers 61
Non - lethal Green night adder 2
Harmless - 29
Others 20
TOTAL TOTAL
Antivenom provided 94 Antivenom provided 94 Antivenom provided 94 Antivenom provided 94

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CLASSIFICATION OF SNAKES

• Medically important snakes can be divided into
  four families
• The Colubridae
• A very large group of snakes
• Non-venomous sand snakes, egg eaters, mole
  snakes (blind snakes), house snakes and bush
  snakes.
• Medically significant snakes in this group are
  the Boomslang and the Vine (Twig) snake
• Their venom is haemotoxic.
• The Elapidae
• This group includes cobras, mambas and coral
  snakes.
• have large hollow fangs at the front of the jaw
• The venom of these snakes is neurotoxic
• Some cobra spit venom that is cytotoxic as well.

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CLASSIFICATION OF SNAKES cont

• The Viperidae
• This group covers adders.
• They have hollow hinged fangs on the front of the
  jaw.
• The venom of this group is mostly cytotoxic some
  species have neurotoxins.
• The Hydrophidae
• This group is composed of sea snakes.
• The venom is neurotoxic (and especially
  myotoxic),
• Most bites are not associated with serious
  envenomation because of their low venom output
  and short fangs .

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VENOM COMPOSITION AND FUNCTION

• Snake venom is one of the most biochemically and
  pharmacologically complex toxins known.
• The most important venom components that cause
  serious clinical effects are
• pro-coagulant enzymes,
• cytolytic or necrotic toxins,
• haemolytic and myolytic phospholipases A2,
• pre- and postsynaptic neurotoxins, and
• haemorrhagins.

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VENOM COMPOSITION AND FUNCTION cont

• Snake venoms vary in their composition from
  species to species but also within a single
  species
• (i) throughout the geographical distribution of
  that species,
• (ii) at different seasons of the year,
• (iii) as the snake grows older (ontogenic
  variation).
• This contributes to the enormous and fascinating
  clinical diversity of snakebites

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FUNCTION OF VENOM

• 1.To immobilize prey
• 2.To digest prey
• 3.To defend from harm

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MECHANISM OF TOXICITY AND ROUTES OF POISONING

• The predominant mechanisms are
• Cytotoxicity,
• Haemotoxicity,
• Neurotoxicity
• Myotoxicity.
• Venom excretion occurs primarily through the
  kidneys
• Some of the complications of envenomation are due
  to nephrotoxicity.

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CLINICAL PATTERNS OF ENVENOMING

• Cytotoxic envenoming
• This is characterized by painful and progressive
  swelling with blood-stained tissue fluid leaking
  from the bite wound, hypovolaemic shock,
  blistering and bruising.
• The victim will complain of severe pain at the
  bite site and throughout the affected limb and
  painful and tender enlargement of lymph glands
  draining the bite site.
• resulting from cytolysis, ischaemia, blood
  extravasations and direct proteolytic activity,
  irreversible death of tissue may occur
  (necrosis/gangrene).

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CYTOTOXIC symptoms
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CYTOTOXIC EFFECTS
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CLINICAL PATTERNS OF ENVENOMING

• Neurotoxic envenoming
• This is characterized by moderate or absent local
  swelling, progressive descending paralysis
  starting with drooping eyelids (ptosis) and
  paralysis of eye movements causing double vision.
• There may be painful and tender enlargement of
  lymph glands draining the bite site.
• The patient may vomit, the saliva may become
  profuse and stringy, and eventually there may be
  difficulties with swallowing and breathing.
• Species involved include black and green mambas
  and non-spitting cobras

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CLINICAL PATTERNS OF ENVENOMING

• NEUROTOXICITY/MYOTOXICITY
• Neurotoxic venoms cause paralysis due to their
  effects on the nervous system.
• predominantly associated with Elapids and
  Hydrophids
• There are two types of neurotoxins
• 1. Neurotoxins of hydrophids bind to post
  synaptic acetylcholine receptors resulting in
  paralysis. Respiratory paralysis is the primary
  cause of immediate death.
• 2. Neurotoxins of Elapids (cobras and mambas)
  have pre-synaptic action which inhibits the
  release of acetylcholine at myeneural junction.

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Neurotoxic Effects
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Neurotoxic effects

• Neurotoxicity from Berg adder Bitis atropos bite
  
• The patient is contracting the (forehead)
  frontalis muscle in an attempt to open his eyes
  despite bilateral ptosis

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Neurotoxicity

• Black mamba bite (Dendroaspis polylepis) showing
  ptosis, external ophthalmoplegia and facial
  paralysis recovering on the day after the bite

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CLINICAL PATTERNS OF ENVENOMING

• Haemorrhagic envenoming
• This is characterized by bleeding from
• the gums
• gastro-intestinal and genito-urinary tracts
• recent and partly healed wounds.
• Species involved include saw-scaled/carpet
  vipers, puff adders, Gaboon and rhinoceros
  vipers, boomslang, and vine snakes.

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Haemorrhagic envenoming

• Saw-scaled viper Echis ocellatus bite, showing
  bleeding from gingival sulci

• Saw-scaled viper Echis ocellatus bite, showing
  bleeding from gingival sulciand into floor of
  mouth

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Haemorrhagic envenoming

• Saw-scaled viper Echis ocellatus bite, persistent
  profuse bleeding from multiple incisions at the
  site of bite inflicted 18 hours earlier

• Saw-scaled viper Echis ocellatus bite on foot 36
  hours previously, persistent bleeding from
  incision made to attach black snake stone

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CLINICAL PATTERNS OF ENVENOMING

• COAGULOPATHIES
• These are
• the most significant
• most unpredictable
• systemic manifestations
• Snakes from all families have been implicated
• Both anti coagulant and pro coagulant properties
  have been described

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SYSTEMIC EFFECTS. Haematotoxicity

• ANTICOAGULATION
• Results from
• i) Interference of activation of clotting factors
• ii) Fibrinolytic and fibrinogenolytic activity.
• iii) Direct or indirect activation of plasminogen
• PRO-COAGULATION
• i) Direct action on phospholipids.
• ii) convert prothrombin to thrombin by cleaving
  appropriate peptides
• THROMBOCYTOPENIA
• Occurs with or without other coagulopathies and
  may result from
• intravascular clotting and consumption of
  platelets
• sequestration of platelets by the venom.
• The degree of thrombocytopenia may directly
  correlate with the severity of envenomation.
• DISSEMINATED INTRAVASCULAR COAGULATION
• Snake venom constituents may interact at various
  points of coagulation cascade to activate
  clotting factors or prothrombin directly.
  Significant amounts of thrombin like enzymes have
  also been identified

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MANAGEMENT OF SNAKE BITES

• Snake venom is primarily intended to assist the
  snake in
• capturing prey
• digestion.
• Its effects are therefore far more effective in
  overcoming prey (e.g. rodents) than humans

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ANTIVENOMS

• Antivenoms are the only effective specific
  treatments or antidotes for snakebite.
• They are raised in large domestic animals
  (usually horses, donkeys or sheep) by
  hyperimmunizing them against a single snake venom
  (producing a monovalent/monospecific antivenom)
  or against venoms of several species of snakes
  whose bites are common and frequently lead to
  severe envenoming in the geographical area where
  the particular antivenom is intended to be used
  (producing a polyvalent/polyspecific antivenom).

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PRODUCTION OF ANTIVENOMS

• The venom of a single species of snake may vary
  in composition and antigenicity.
• As a result, pooled venom from many (20-50)
  individual specimens of each snake species should
  be used for antivenom production.
• These individuals should come from different
  parts of the geographical range and should
  include some younger (smaller) specimens to take
  these factors into account.

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PRODUCTION OF ANTIVENOMS

• After animals have completed the immunization
  schedule, plasma is collected, preferably by
  plasmapheresis (so that the red blood cells can
  be returned to the donor animal) and is passed
  through several processes designed to produce
  either
• refined whole IgG antibodies or
• IgG antibody fragments such as F(ab')2 or Fab,
  which are free of other plasma proteins such as
  albumin, fragments such as Fc, aggregates (a
  major cause of antivenom reactions), pyrogens and
  microbes.
• It is then either lyophilized or stored as a
  liquid.

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USE OF ANTIVENIN

• Antivenom neutralizes a fixed amount of venom.
• Since snakes inject the same amount of venom
  into adults and children, the same dose/volume of
  antivenom must be administered to children as to
  adults.
• Antivenom can be effective as long as venom is
  still active in the patients body causing
  symptoms of systemic envenoming.
• These may persist for several days or even weeks
  after the bite (e.g. incoagulable blood and
  bleeding after saw-scaled viper bites).

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INDICATIONS FOR ANTIVENOM

• When used correctly, antivenin can effectively
  reverse systemic poisoning
• Antivenin should not be administered routinely in
  all cases of snake bites as it can cause severe
  acute reactions or fatality.

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Indications for antivenom treatment after bites
by African snakes

• Systemic envenoming
• 1. Neurotoxicity
• 2. Spontaneous systemic bleeding
• 3. Incoagulable blood (20MWBCT)
• 4. Cardiovascular abnormality hypotension,
  shock, arrhythmia, abnormal electrocardiogram
• Local envenoming by species known to cause local
  necrosis
• 1. Extensive swelling (involving more than half
  the bitten limb)
• 2. Rapidly progressive swelling
• 3. Bites on fingers and toes
• Bitis, Echis, Cerastes, Macrovipera spp. and
  spitting cobras

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Sources of antivenom

• There is great concern about the supply of
  antivenom for Africa.
• Several Indian producers, including Serum
  Institute of India (SII), Vins Bioproducts and
  Bharat Serum and Vaccines Ltd. (Asna Antivenom),
  export antivenoms to Africa.
• The clinical efficacy and safety of these
  antivenoms needs to be established. Confirm that
  the venoms used for their production are from
  African and not Asian snake species.
• Beware of misleading labelling implying that they
  have activity against African rather than Asian
  cobra and saw-scaled viper venoms

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Resolutions from Dakar Conference (April 2011)

• 1. Snake and scorpion bites exist and need to be
  handled urgently and competently.
• 2.Need for Epidemiological Surveys.
• 3.Training of Health Workers  (Inclusion in the
  Medical Curriculum).
• 4.Need for individual country capacity building.
• 5. Address the issue of FAKE and unsuitable
  antivenoms.
• 6. Joint procurement by countries in a given
  regional block from one regional producer to
  ensure price reduction.
• 7. Feedback meetings.
• 8. Intense Pharmacovigilance by relevant
  government authorities.
• 9. Funding for production or purchase of
  antivenoms through subsidies.
• 10. Collaboration with Traditional Healers and
  more research into their Herbal preparations