'Quinidine-like' Effects, 'Membrane-stabilising' Properties or 'Non-specific Toxicity'
Articles and texts on poisoning often refer to toxins having 'quinidine-like' effects, 'membrane-stabilising' properties or 'nonspecific toxic effects' despite the lack of any clear knowledge of the underlying mechanism that leads to a wide range of observed effects on cardiac conduction by a structurally diverse group of drugs.
Based loosely on the Overten-Meyer hypothesis concerning inhalation anaesthetics, Cassidy & Henry (& others) postulated that a number of adverse effects of drugs in overdose (particularly coma, seizures and arrhythmias) were due solely to their dissolution in cell membranes. This led, it was hypothesised, to interference with all functions of cell membranes, in particular the normal function of ion channels. There is a loose correlation between the lipid solubility of some selected drugs and their fatal drug concentrations but no experimental evidence to support the hypothesised 'nonspecific' nature of the effects on ion channels.
There is a great deal of evidence against this theory.
It is easy to find examples of highly lipid soluble drugs for which these effects are rare (a number of the antihistamines) and there are examples of water soluble drugs with significant effects on membrane channels (lithium and sotalol).
The type of ion channels affected varies between drugs - such that some drugs only appear to affect depolarisation (presumably Na+ channels) and some appear to affect repolarisation (presumably K+ channels). The production of seizures varies markedly between drugs even within a drug class such as TCAs and does not correlate highly with lipid solubility. Amoxapine has been shown to cause seizures through direct antagonism of GABA receptors.
There is much other evidence to suggest that there is a great deal of heterogeneity in the effects on ion channels and the clinical effects produced by drugs with 'membrane-stabilising' effects. For example, adrenaline protects against arrhythmias in chloroquine poisoning but precipitates arrhythmias in amitriptyline poisoning. As another example, the kinetics of imipramine and desipramine binding to Na channels are markedly different.
Thus, it seems likely that, just as the Overten-Meyer hypothesis has been disproved, all these poorly described toxic effects will be found to be due to specific binding to a number of different cell membrane proteins (receptors and ion channels) and the affinity of drugs for different proteins will vary considerably.
The importance of understanding this is that there should be no expectation that treatments effective for one drug with 'membrane-stabilising' properties will necessarily be effective for another drug, even from the same therapeutic class (as toxic effects of drugs are usually not related to their therapeutic action).
Henry JA, Cassidy SL. Membrane stabilising activity: a major cause of fatal poisoning. Lancet 1986 Jun 21;1(8495):1414-7