Pharmacology and Therapeutics

Transient hypotension has been observed in human victims of Australian elapid snake bite. Its aetiology and mechanism are unknown. This thesis concerns the study of the cardiovascular, coagulation and haematological effects of Brown snake (Pseudonaja spp) and Tiger snake (Notechis scutatus) venom and procoagulants derived from both. Whole venom from Pseudonaja textilis, Pseudonaja affinis and Pseudonaja nuchalis induced severe depression of cardiovascular function after intravenous and subcutaneous injection in anaesthetised mechanically ventilated dogs. The hypotension occurred within several minutes of intravenous injection and within fifteen minutes, sometimes sooner after subcutaneous injection, and persisted for approximately 30 minutes. It was accompanied by diminution in cardiac output and stroke volume and by increases in heart rate, pulmonary artery pressure, pulmonary artery occlusion pressure, central venous pressure and by increases in peripheral and pulmonary vascular resistances. Electrocardiographic signs of myocardial ischaemia occurred during hypotension. These observations are consistent with acute biventricular cardiac failure. Coagulation and haematological studies during cardiovascular depression revealed evidence of disseminated intravascular coagulation which consisted of prolongation of prothrombin and activated partial thromboplastin times and depletion of serum fibrinogen. Fibrinolysis was not detected up to two hours after envenomation. Thrombocytopenia and leucopenia were observed. Limited post-mortem examinations revealed fluidic blood in the major thoracic and abdominal vessels. Small haemorrhages were observed within or on the surfaces of the lungs, kidneys, liver and spleen. However, the magnitude and extent of the haemorrhages were not considered to be the cause of hypotension. Macroscopic thrombi were observed in the heart chambers including the left ventricle. The cardiovascular and haematological effects of the whole venoms were duplicated by intravenous infusion of procoagulants (prothrombin activators) purified from Pseudonaja textilis venom and from Notechis scutatus venom. The effect of heparin on the activities of Pseudonaja textilis prothrombin activator and to a lesser extent on Notechis scutatus prothrombin activator was also studied. Prior administration of heparin prevented the systemic and pulmonary haemodynamic effects of both prothrombin activators. These observations support the concept that cardiovascular depression is a consequence of coagulopathy, but do not exclude other causes including direct depression of cardiac function by the venom or by vasoactive substances released by the venom. Heparin therapy was ineffective in treatment of established Pseudonaja textilis envenomation. The cardiovascular and haematological effects of whole venom were neutralized by Brown snake antivenom but in doses well in excess of those currently recommended for clinical treatment of human snake bite victims. Echocardiographic studies revealed formation of multiple thrombi within the cardiac chambers during intravenous administration of Notechis scutatus prothrombin activator. This was associated with pulmonary hypertension, right heart dilatation, impeded filling of the left heart and by systemic hypotension and low cardiac output. Histological sections of lung revealed thrombi within the pulmonary circulation. Although the coagulation process is known to release vasoactive substances from platelets which may cause pulmonary hypertension and systemic hypotension, no evidence of involvement of platelet activating factor, thromboxane A2 or other eicosanoids, serotonin or histamine could be demonstrated. Pulmonary hypertension was not responsive to inhaled nitric oxide. It was concluded that systemic hypotension was a consequence of thrombo-embolic obstruction of the pulmonary circulation and may explain transient hypotension sometimes observed in humans after Pseudonaja or after Notechis envenomation. This phenomenon may be exacerbated by depression of myocardial contractility as a consequence of coagulation in coronary vessels with subsequent ischaemia.

Although severe and occasionally fatal results have followed the bite of spiders and the sting of fish in Australia, relatively few investigations have been carried out in the past on the venom the species of animals responsible for them. Antivenens have been produce against the venom of various species of spiders belonging to the genus Latrodectus in other parts of the world, but no attempt has been made in the past to produce an antivenene against the venom of the red-back spider which is the Australian representative of this genus. With the venom of the Sydney funnel-web spider, previous investigators have not been able to demonstrate any toxic effects in laboratory animals. Only a few studies have been carried out with the venom of the stone-fish but no attempt to produce an antivenene has been made. Treatment of envenomation following an effective bite or sting by these animals has therefore remained empirical and in the absence of a specific antivenene was not very successful. The present investigation was undertaken with the view to producing a specific antivenene against the venom of the red-back spider (Latrodectus hasseltii), the venom of the funnel-web spider (Atrax robustus) and the venom of the stone-fish (Synanceja trachynis) respectively. The studies presented in this thesis were therefore primarily concerned with the accomplishment of a practical task for which no efforts were spared. (From Introduction)

Pharmacology and Therapeutics - Theses

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