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Autopharmacological venom/poison effects

Definition: Systemic effects caused by the release/formation of endogenous autacoids or autacoids contained in the venom/poison.

 

Autacoids include certain biogenic amines, lipid derivatives, peptides and purine compounds (Grundy 1990). The primary autacoids that are associated with envenoming/poisoning by animals are the biogenic amines histamine and serotonin, bradykinin, lysophosphatides and prostaglandins. Other mediators, in particular catecholamines, are discussed in the section "Neurological venom/poison effects".

 

Signs and symptoms:

  • skin reactions (erythema, urticaria, angio-oedema),
  • nausea, vomiting,
  • sweating,
  • colic,
  • diarrhoea,
  • asthma,
  • arterial hypotension (transient, recurrent and persistent),
  • anaphylactic shock,
  • hypovolaemic shock (generalised increase in capillary permeability).

The above symptoms and signs of envenoming/poisoning can occur as a result of the release of endogenous autacoids or autacoids contained in the venom/poison. They usually occur early in the course of envenoming/poisoning. The underlying pathomechanisms are for the most part based on animal or in vitro experiments. With regard to humans, they are largely speculative.

 

The following types of autopharmacological reactions can be distinguished:

Allergic reaction (specific pre-sensitisation)

Pre-sensitisation to specific venom/poison components leads to a classic immediate-type allergic reaction or type 1 reaction upon renewed contact (Roitt et al. 1985). IgE-mediated mast cell degranulation leads to histamine release (Fig. 5.1) and as a consequence to an anaphylactic reaction.

With regard to allergic reactions to animal venoms/poisons, the hymenopterans (in particular bees and wasps) have the greatest significance, but such reactions also occur in envenoming/poisoning caused by snakes, jellyfish and other animals. The most important allergen in bee venom is phospholipase A₂, but also hyaluronidase (Müller 1988). Both enzymes are also very commonly found in other animal venoms/poisons, in particular snake venoms. The question as to what extent "cross-allergies" are possible is still unresolved.

Following accidents with jellyfish, it is relatively common for delayed skin reactions to occur (after 5–30 days). These are type IV allergic reactions (delayed-type hypersensitivity) (Roitt et al. 1985, Ohtaki et al. 1986, 1990, Burnett et al. 1987, Piérart et al. 1990), whereby venom/poison components that probably remain deposited in the skin for an extended period of time cause the activation of T cells and the release of lymphokines. This leads to a delayed-type inflammatory reaction with the activation of macrophages and the release of autacoids.

Anaphylactoid or pseudo-allergic reactions (without pre-sensitisation)

Effects that are similar to those of the spectrum of anaphylactic disorders through to anaphylactic shock can also occur in the absence of pre-sensitisation. They are caused by the release or formation of endogenous autacoids or by biogenic amines contained in the venom/poison.

 

Venom/poison-mediated release of endogenous autacoids (mast cell degranulation)

Phospholipase A, an enzyme commonly found in animal venoms/poisons, has an indirect degranulating effect on mast cells. It causes the release of lysophosphatides from plasma membranes, which in turn leads to degranulation of mast cells.

There are other protein venom/poison components that act directly on mast cell membranes to cause the release of histamine. Such components include melittin and mast cell-degranulating peptide (MCD), contained in bee venom, crotamine from the venom of the Cascavel (Crotalus durissus terrificus) and other as yet poorly characterised proteins from crotalids and viperids, and direct lytic factor (DLF), a polypeptide from the venom of Asiatic cobras (Naja sp.).

Melittin and MCD do not appear to cause any systemic effects and are most commonly associated with local venom/poison effects. With regard to the above-mentioned snake toxins, it has not been clarified whether they lead to systemic effects.

Cobra venom factor (CVF), a non-enzymatic protein from cobra venoms (Naja naja, N. kaouthia, N. atra, N. haje and N. nigricollis), leads to activation of the complement system through the conversion of C3 and C5 into the anaphylatoxins C3a and C5a. In turn, the anaphylatoxins cause histamine to be released from mast cells via degranulation.

However, as anaphylatoxins are rapidly inactivated by serum carboxypeptidase B, neither local nor systemic effects are likely to occur.

 

Formation of endogenous autacoids

Besides the modes of action described above, DLF also appears to activate phospholipase A (endogenous or contained in the venom/poison) to cleave cellular phospholipids. From the lysophosphatides thus created, prostaglandins (slow-reacting substances) are formed via tissue prostaglandin synthetase. However, prostaglandins can probably also be formed solely through the activity of phospholipase A even in snakes whose venom does not contain DLF.

Several arginine ester hydrolases, such as are commonly found in crotalid and viperid venoms, can act as kininogenases and thus convert kininogen into bradykinin. Along with histamine release, this mechanism appears to be responsible for the extensive local oedema that is typical of crotalid and viperid bites. In support of this is the fact that in elapids, whose bites cause far less severe local reactions, kininogenase activity is generally not observed.

If large amounts of bradykinin-forming venoms/poisons enter the circulation, it is quite possible that they could cause transient hypotensive states, such as occur early in the course of envenoming, especially with bites from the viper genus Vipera. Simultaneous release of histamine would amplify such an effect. Moreover, in some crotalids and viperids (Bothrops jararaca, Gloydius blomhoffi, Vipera palaestinae, among others), bradykinin-potentiating factors (angiotensin-converting enzyme inhibitors) have also been found, which lead to an increase in bradykinin release. Bradykinin-potentiating factors have also been found in spiders (Latrodectus tredecimguttatus) and scorpions (Buthus occitanus, Leiurus quinquestriatus and Tityus serrulatus) (Ferreira et al. 1993).

 

Autacoids as venom/poison components

The most important autacoids in animal venoms/poisons are histamine and serotonin. Histamine is found primarily in hymenopteran venoms (bees, wasps, hornets and ants), but also in the pit viper Trimeresurus mucrosquamatus (=Protobothrops mucrosquamatus) (Müller 1988, Tu 1977). However, because there is only a small amount of histamine contained in these venoms, it is only likely to contribute to local symptoms. Poisoning caused by scombrotoxic fish is quite a different matter, however, as in this situation histamine is present in larger amounts as a bacterial product of decomposition in the musculature of dead fish, and following consumption, can lead to typical histamine poisoning.

Serotonin is contained in the venom of scorpions, spiders, wasps and hornets, in the Gila monster (Heloderma sp.) and in very small quantities in some crotalids and viperids as well (Tu 1977). It is conceivable that serotonin in venom could contribute to local effects.


Literature: Grundy 1990, Mebs 1990b, Minton 1974, Rothschild and Rothschild 1979

 

Figure 5.1 Autopharmacological venom/poison effects. Simplified representation of the pathomechanisms.