An alternative antidote therapy in amitriptyline-induced rat toxicity model: theophylline

Abstract

We planned this study in order to investigate the effects of theophylline on cardiovascular parameters in an anaesthetized rat model of amitriptyline toxicity. In the preliminary study, we tested theophylline as 1 mg/kg of bolus, followed by a 0.5-mg/kg infusion. Toxicity was induced by the infusion of 0.94 mg/kg/min of amitriptyline up to the point of a 40-45% inhibition of mean arterial pressure (MAP). The rats were randomized to two groups: a group of 5% dextrose bolus followed by 5% dextrose infusion, and another group with theophylline bolus followed by infusion. Amitriptyline caused a significant decrease in MAP and prolongation in QRS; however, it did not alter heart rate (HR). When compared to the dextrose group, theophylline administration increased MAP, shortened prolonged QRS duration, and increased HR (P < 0.05, respectively). There was no statistically significant difference in the results of arterial blood-gas analyses among the groups (P > 0.05). Bolus doses followed by a continuous infusion of theophylline were found to be effective in reversing the hypotension and QRS prolongation seen in amitriptyline toxicity. One of the possible explanations of this beneficial effect is nonselective adenosine antagonism of theophylline. Further studies are needed to reveal the exact mechanism of the observed effect.

The effects of diltiazem and metoprolol in QTc prolongation due to amitriptyline intoxication

“…Despite the mechanism not being clear completely; in literature, there are some studies that tried some agents such as adenosine A1 receptor antagonist, theophylline, glucagon, lidocaine, or phenytoin and found good effects on cardiotoxicity of amitriptyline. 7,18,19,24 In this study, besides presentation of ECG abnormalities as particularly QTc prolongation, the effects of both metoprolol and diltiazem were investigated. According to the results, it is found that both of them shortened QTc and T duration prolongation.…”

“…Despite the mechanism not being clear completely; in literature, there are some studies that tried some agents such as adenosine A1 receptor antagonist, theophylline, glucagon, lidocaine, or phenytoin and found good effects on cardiotoxicity of amitriptyline. 7,18,19,24…”

Effects of BQ-788 on amitriptyline-induced cardiovascular toxicity

“…3 Some investigational treatment modalities such as L-NAME, a NO synthase inhibitor, selective adenosine A 1 and A 2a receptor antagonists, glucagon or theophylline were reported to be effective in reversing amitriptylineinduced hypotension in animal models. 8,[12][13][14] ETs, which are powerful vasoconstrictor peptides, show their effects via their receptors entitled ET A and ET B . While ET A receptors are responsible for vasoconstriction and increase in blood pressure, ET B receptors cause vasodilatation by the secretion of NO and prostacycline.…”

“…3 Some investigational treatment modalities such as L-NAME, a NO synthase inhibitor, selective adenosine A 1 and A 2a receptor antagonists, glucagon or theophylline were reported to be effective in reversing amitriptyline-induced hypotension in animal models. 8,12 –14…”