Menge T. B. B. Pharm; M.Sc (Pharmacology & Toxicology) UPDATES ON VACCINES ANTISNAKE VENOM.

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Menge T. B. B. Pharm; M.Sc (Pharmacology & Toxicology) UPDATES ON VACCINES ANTISNAKE VENOM

Transcript of Menge T. B. B. Pharm; M.Sc (Pharmacology & Toxicology) UPDATES ON VACCINES ANTISNAKE VENOM.

Menge T. B.B. Pharm; M.Sc (Pharmacology & Toxicology)

UPDATES ON VACCINESANTISNAKE VENOM

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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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EPIDEMIOLOGYIt 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. 2008Total No. of cases = 76Treated with antivenom = 21 (but query on 3 cases)Fatalities = 1

Bioken, Watamu, Kenya Nov. 1997 - Nov. 2007Species

Dangerous Puff adders 33 (2 fatal)

Cobras 17 (3 fatal)

Black mamba 5 (2 fatal)

Green mamba 6

Boomslang 2 (1 fatal)

Twig snake 1

Venom in eyes 11

Non - lethal Mole vipers 61

Green night adder 2

Harmless - 29

Others 20

TOTAL

Antivenom provided: 94

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CLASSIFICATION OF SNAKESMedically important snakes can be divided into

four familiesThe 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 jawThe venom of these snakes is neurotoxic Some cobra spit venom that is cytotoxic as well.

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CLASSIFICATION OF SNAKES cont’

The ViperidaeThis 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 HydrophidaeThis 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 prey2.To digest prey3.To defend from harm

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MECHANISM OF TOXICITY AND ROUTES OF POISONING

The predominant mechanisms are; Cytotoxicity, Haemotoxicity, NeurotoxicityMyotoxicity.

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 envenomingThis 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

CLINICAL PATTERNS OF ENVENOMINGNeurotoxic 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

Neurotoxic effectsNeurotoxicity from Berg adder Bitis atropos bite:

The patient is contracting the (forehead) frontalis muscle in an attempt to open his eyes despite bilateral ptosis

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

CLINICAL PATTERNS OF ENVENOMINGHaemorrhagic envenomingThis 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.

Haemorrhagic envenomingSaw-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

Haemorrhagic envenomingSaw-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 ENVENOMINGCOAGULOPATHIESThese 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

ANTICOAGULATIONResults from:i) Interference of activation of clotting factorsii) Fibrinolytic and fibrinogenolytic activity.iii) Direct or indirect activation of plasminogen

PRO-COAGULATIONi) Direct action on phospholipids.ii) convert prothrombin to thrombin by cleaving appropriate peptides

THROMBOCYTOPENIAOccurs 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 COAGULATIONSnake 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

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).

PRODUCTION OF ANTIVENOMSThe 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.

PRODUCTION OF ANTIVENOMSAfter 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 patient’s 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 ANTIVENOMWhen 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.

Indications for antivenom treatment after bites by African snakesSystemic envenoming

1. Neurotoxicity2. Spontaneous systemic bleeding3. Incoagulable blood (20MWBCT)4. Cardiovascular abnormality: hypotension, shock,

arrhythmia, abnormal electrocardiogramLocal envenoming by species known to

cause local necrosis*1. Extensive swelling (involving more than half the

bitten limb)2. Rapidly progressive swelling3. Bites on fingers and toes

*Bitis, Echis, Cerastes, Macrovipera spp. and spitting cobras

Sources of antivenomThere 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

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