sodium channels and, as with every drug (in mammals), one or more cytochrome P450 enzymes. I wont discuss the latter, since they were the subject of a previous MOTM post. Just pause for a moment and think of the remarkable speed with which lidocaine acts after an injection. I am immediately reminded of a conversation with Dr. Rob Harrison at the Liverpool of Tropical Medicine, as we paused in front of one of his splendid collection of snakes: the Green Mamba. Rob's life work has been devoted to understanding the science of snake bites! The Green Mamba, a particularly unsociable, venomous snake, produces a rapid acting, but lethal venom. In some cases, the infiltration of the blood stream with its cocktail of neurotoxins and cardiotoxins, can lead to death in 30 minutes! This is exactly what happens with lidocaine: well not the death bit! Which brings me to the -caine part of lidocaine. It is of course related to cocaine, the recreational drug that preceded drugs like lidocaine in surgery. Cocaine rapidly induces euphoria, but importantly for medicine, it was an early anaesthetic, or numbing agent. Lidocaine combines the anaesthetic properties of cocaine, with the cardiovascular properties of many venom toxins.
When a patient presents with a cardiac arrhythmia, (such as ventricular tachycardia (LHS) drugs like lidocaine have traditionally been employed to restore normal heart rhythm. Today, there is a different protocol associated with advanced cardiac life support (ACLS): typically through the widespread distribution and training in the use of defibrillators, the restoration of normal heart rhythm is done at the site of "attack" by trained first aiders or by paramedics. However, from a molecular physiology perspective; what's happening? Lidocaine acts to prevent conduction of impulses along the nerve fibres. Such impulses rely, as do cardiac contractions, on the proper functioning of sodium channels.
There is no crystal structure available yet of lidocaine bound to a sodium channel, but indirect binding experiments on wild type and mutant forms of such channels suggests that lidocaine makes potent interactions with the two major conformational states (open and closed) of sodium channels. In the diagram opposite, two key residues that mediate the lidocaine interaction are shown. You can read an open access article from Dorothy Hanck at the University of Utah, here). In finishing, it seems fascinating to me that molecules such as lidocaine can have such a rapid effect on the cardiovascular system of a relatively large organism. An integral membrane channel that selectively handles a small ion, fortuitously captures molecules like lidocaine and the normal rapid electrical processes are dissipated. It also suggests to me that by investigating the properties of naturally occurring toxins, such as those found in snake venom, we may be able to understand the complexity of cardiovascular and nervous "systems", but also, we find some useful drugs.