Pharmacodynamics of Snake Venoms and Envenomation
by
Lee Moore

Introduction 

This paper is not intended as an all-inclusive presentation of all components of snake venoms nor does it propose to explain all the physiological processes involved in snake envenomation.
Rather it is intended as a brief introduction and description of the biochemical mechanisms involved during snake envenomations in general. It attempts this from an innovative and simplistic perspective.

It should be pointed out here, that the previously established practice of classifying a venom as either hematoxic or neurotoxic has proven to be flawed and insufficient in defining the true nature of snake venoms and toxins. Since the establishment of the International Society on Toxinology and publishing of its interdisciplinary journal of toxins, TOXICON,   there has been a source of shared information that has helped to provide some standardization. However, there is still a problem with general classifications. Toxins are often termed according to the emphasis of the study in which they are identified.  Cardiotoxins, as an example, can be a cytotoxin that has proven to have considerable effects on the cardiac muscle cells, or a Myotoxin that specifically affects the heart.  It may be that these generalizations cannot be avoided or may even be necessary since the effects of toxins are certainly dependant on a number of factors exogenous and endogenous to the physiology of the host. Toxins cannot be expected, except under controlled situations, to always react with the same effects. However with this generalization of terms it is necessary to have a broad knowledge of all the potential specifics.

Snake venoms are composed of various collections of polypeptides. These polypeptides are toxins that or either enzymes or non-enzymatic polypeptides. The effects or actions of these toxins are, on the most part, either by a means of degradation of cells, tissues and/or intercellular bonds or by a competitive inhibition blocking transmission of acetylcholine. Exceptions to this is found in all species belonging to the genus Dendroapsis, snakes known as mambas.

Other venom components have been identified including carbohydrates, lipids, nucleoside and some metals. Magnesium, calcium, and zinc are the most prevalent metals, copper has been detected in some venoms. There are studies that suggest that some of these co-constituents may play an active role in the lethality of venoms.  The purpose of this paper is not to present validity to, or to dispute any such finding. However, it is the opinion of this author, that though there probably is validity in these findings the importance of these substances to effect toxicity would probably be academic, because such substances are either endogenous to the host or indigenous, in some way, to the envenomation itself.

Enzymes 

Though most snake venoms have enzymes that act as toxic constituents, all are composed of several enzymes. More than 20 enzymes have been detected in snake venoms, and 12 are found in all venoms. The majority of toxic effects of viperid and crotalid (pit vipers, including rattlesnakes moccasins, etc.) envenomations are due to enzymes collectively termed “proteases”. These are actually hyrdolases that primarily act to breakdown proteins, by hydrolysis and thus are proteolytic and serve a digestive role.  They are also the cause of most of the local damage following envenomation. These enzymes are further separated and classified according to the mode or target site of their actions, for instance endo - and exopeptidases. These target bonds in the peptide chains that hold proteins together. One of the enzymes that are present in all snake venom is Hyalurondase. It is present in viperid, crotalid, elapid and hydrophid venoms, as well as in most animal venoms. Its effect can readily be observed following envenomation as blood oozing from the bitten site. This is the first good indication that can be observed, following a bite, to determine if an envenomation has occurred. The absence of this oozing is a possible indication that no or little venom was injected.  Hyalurondase is known to have a “spreading action”. It is the first enzyme to take action by facilitating other venom components through tissues and into the bloodstream. It greatly increasing permeability of membranes, ruptures cellular walls and alters coagulation. In a sense it acts as a “ vehicle” to provide active transport for other toxic components.

It is not only the snake toxins itself that exerts toxic effects, but also the products that are produced by the digestive process of the enzymes. Such is the case involving the phospholipases that produces lytic products by cleaving membrane-bound phospholipids.  Another example of this involves L-Amino-acid oxidase, which is another found in all snake venoms. It causes the release of the powerful lytic chemical hydrogen peroxide. Its toxic effect is by oxidation of cells.

In cases involving venoms that exerts their primary toxic effects as a neurotoxin,  affecting neuromuscular processes, it is not  enzymes, but other non–enzymatic polypeptides that act as the primary lethal agent. However, enzymes, always play an active role in facilitating the spread of  these non-enzymatic polypeptides.

PROTEOLYTIC OR HEMOLYTIC? 

Snake venom enzymes are proteolytic and hemorrhagic toxins.  These cause hemorrhage by targeting fibrinogen converting it by digestion into an unclottable substance or by directly causing lysis of blood cells. Blood platelets and Prothrombin are also sometimes affected leading to coagulopathy of sorts and even hemorrhage. Ultimately hypovolemia can result in any case.  Constituents have been found in snake venoms that have activating and inactivating effects on nearly all aspects of hemostasis. Some studies have indicated that some of these hemorrhagic toxins may not be enzymatic in nature. However, most are certainly enzymes. In contrast to causing hemorrhage, some toxins has been found to act in the same path as human endogenous clotting factors, but in the cases of these exogenous agents there are no controlled corresponding inhibitors. A notable example is the Russell’s viper Daboia Russelli.  Its venom causes severe coagulopathy by preventing coagulation then activating uninhibited coagulation. Much research using this venom has already revealed uses to further understand human clotting factors and control coagulopathy disorders.

The method by which proteolytic toxins digest proteins is not entirely different than what occurs during hemolysis. In both cases there is lysis causing cellular and tissue destruction by the some means of degradation.  The question, or rather an observation may arise, what differentiates a proteolytic toxin as opposed to a hemolytic one? Perhaps what actually constitutes the difference is the level at which the lytic damage is noted. 

MYOTOXINS and CARDIOTOXINS 
 

Cytolytic or Hemolytic? 

Whereas many, if not all, toxic venom enzymes can prove to be toxic to muscle during envenomation there are also toxins that have been determined as specific myotoxins. These are basically cytotoxins that cause damage to muscle cells. Many cardiotoxins are cytotoxins that have been found to exert specific damage to cardio cells.   The toxin that is cytolytic is certainly also hemolytic. A hemolytic or cytolytic toxin certainly has potential as a myotoxin or cardiotoxin.

Neurotoxins

Summary 

Though the natural primary purpose of venom is primitive in nature, serving to secure prey and for defense, more clues to understanding its agents and reactions are more easily understood, when their subsequent purposes are contemplated. The first of these, which is relevant to securing of prey, is the immobilization of its prey. It is here where complex processes occur that prevent the ordinary physiological functions that maintain homeostasis. The velocity at which these agents reach the intended physiological targets and accomplish their purpose is a subject that evokes wonder. The processes and their results are comparable to a lock or switch, that when turned either prevents physiological processes by locking out  receptors or by unlocking and releasing agents that results in a malfunction. The individual toxins work together in a dynamic way to facilitate the processes and functions in the whole venom. Further investigation and understanding of these processes can provide a wealth of information about ordinary physiological processes and potential means of controlling them.

Barrett and Harvey  (1979) Effects of the Green Mamba. Br. J. Pharmacol 67:1. 99-105

Harris, J.B. (1991) Phospholipases in snake venoms and their effects on nerve and muscle Snake Toxins pp91-129 editor Harvey

Harvey and Anderson   (1991) Dendrotoxins: Snake Toxins       pp131-164 editor Harvey

Hider, Karlsson, Namiranian (1991) Snake Toxins pp1-34 editor Harvey

Kabara, J.J. and Fisher, G.H. Chemical compaosition of Naja naja venom Toxicon, 7 223 1969

Kornalik, F.   (1991) The influence of snake venom on coagulation Snake Toxins pp323-833 editor Harvey

Menez, Andre    (1991) Immunology of snake toxins Snake Toxins pp35-90 editor Harvey

Mobs, D. (1969) Preliminary studies on small molecular toxic components of elapid venoms Toxicon 6:247-253

Seegers and Ouyang (1979) Snake venoms and blood coagulation Snake venoms Handbook of experimental Pharmacology 52:684-750, Lee, C.Y. editor

Ownby, C.,  (1990) Locally acting agents Handbook of Toxinology, 601   Shier, W.T., Mebs, D. editors Marcel Dekker, New York

Timbrell, J.A.(1995) Introduction to Toxicology School of Pharmacy University of London

Zeller, E. A. (1977) Snake venom action: Are enzymes involved in it? Experientia 33:143-150

"It should be pointed out that my finger is bent as a result of the skin graft treatment.  The skin graft required my finger to be immobilized and splinted while the graft took, which it did not take!

This immobilization caused the tendons to tighten up. Snake bites of Extremities should be allowed to move and stretch.  Contracture of muscle and tendon is probably the most common permanent effect following a venomous snakebite to an extremity.  This is further complicated by fixation of joints and muscles.  Localized scars, are not preventable, however, improper first aid treatments can greatly ad to the severity of the scar.

My finger should have been debried shortly after the bite, allowing for continual removal of subsequent sloughing of tissue.  This would have allowed flexation and movement. Complication of tightened tendons can be remedied by surgically cutting the tendon.

I didn't hold the physicians responsible since treatment for other injuries can effectively be achieved using this procedure. Even snake bites can be treated like this, but with more complications and a longer recovery.

An argument in favor of a skin graft could well be made.  Pointing out that in cases such as this, when due to tissue damage and subsequent debriment, exposes cartilage and tendon or a large area of subcutaneous fascia. Such a wound warrants concern for infection and or drying could be considered for a graft.  Applicably the graft serves as a “bandage” or even if the graft doesn’t take, as a “scab” to protect from further exposure.  However, this can also be accomplished with proper bandage and treatments.

In my opinion, the later is the best method of treatment whenever possible.

Lee Moore, Jr.  1/25/03

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ANTI-VENOM

Two types of anti-venom are produced by Wyeth Laboratories for treatment of envenomations caused by native venomous snakes in North America. Wyeth produces Crotalidae Polyvalent Antivenin® to treat crotalid envenomations. This anti-venom covers all envenomations except from bites of coral snakes. Coral snakes envenomation requires Antivenin (Micrurus fulvius).

These medications are designed to provide a broad spectrum of effectiveness. However these medications are known to better neutralize some venom more effectively than others.   This is due to the fact that not all species are used in the production of anti-venom and in the cases of some species the effectiveness relies on a cross resistance provide by the antibodies produced by other similar toxins.

Wyeth Laboratories can be contacted at P.O. Box 8299 Philadelphia, Pa. 19101-1245 U.S. (215) 688-4400.