The antidotal effect of alpha(1)-acid glycoprotein on amitriptyline toxicity in cardiac myocytes.
Tricyclic antidepressants in overdose cause toxicity marked by prolongation of the QRS interval of the electrocardiogram. These drugs are bound to alpha(1)-acid glycoprotein (AAG) with high affinity in plasma. Animal studies have shown that the administration of AAG shortens the QRS prolongation induced by tricyclic antidepressants. In order to clarify the pharmacological mechanism involved and to obtain clinically relevant evidence at the cellular level, whole-cell patch clamp techniques were performed in single guinea-pig ventricular myocytes to elicit the time and voltage-dependent fast sodium currents using both normal and modified physiological solutions. Cells stayed viable for much longer when they were placed in normal physiological solutions, providing sufficient recording time for consistently reproducible, clinically relevant toxicological results to be obtained. Amitriptyline (AMI) produced a concentration-dependent blockade of sodium currents with an approximate IC(50) of 0.69 microM. AAG reversed this blockade in a concentration-dependent fashion at concentrations ranging from 3.2 to 12.8 microM. Using the same experimental conditions, AAG also reversed the blockade of sodium current by quinidine, a class I antiarrythmic drug. Albumin did not reverse the blockade of sodium channels by AMI. The results indicate that AAG is a potential antidote for tricyclic antidepressant overdose.
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Academic Department of Accident and Emergency Medicine, Imperial College School of Medicine, St. Mary's Hospital, W2 1NY, London, UK. y.ma@ic.ac.uk
Henry
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JA
D000465:Algorithms; D000639:Amitriptyline / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000931:Antidotes / Q000494:pharmacology*; D004569:Electroencephalography / Q000187:drug effects; D004594:Electrophysiology; D006168:Guinea Pigs; D006331:Heart Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000473:pathology*; D009961:Orosomucoid / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011802:Quinidine / Q000494:pharmacology; D026941:Sodium Channel Blockers
D000929:Antidepressive Agents, Tricyclic; D000931:Antidotes; D009961:Orosomucoid; D026941:Sodium Channel Blockers; D000639:Amitriptyline; D011802:Quinidine