Tuesday, 1 December 2015

Molecule of the Month for December: Lidocaine

Lidocaine-from-xtal-3D-balls.pngLidocaine (sometimes called lignocaine or xylocaine) is a drug that was first synthesised just over 70 years ago by the Swedish chemist Nils Lofgren (for those of you of a musical bent, you may like me enjoy the beautifully understated guitar playing of the founder of Grin,  who enjoys a solo career and also accompanies both Neil Young and latterly, Bruce Springsteen. My favourite example of his guitar work is on the track Speakin' Out from the Neil Young and Crazy Horse album entitled Tonight's the Night, you can find it on YouTube). Anyway, back to drugs! Lidocaine was originally introduced as an anaesthetic 70 years ago and later became popular for treating patients presenting with a number of heart problems.The reason I decided to write about lidocaine is two-fold. The first is its extraordinary, rapid action: it is effective within two minutes after injection (fizzling out after about 20 minutes). The second is its target: a group of sodium channels. Sodium channels (as the name suggests) regulate the passage of Na+ ions across cell membranes and play a key role in nerve transmission and governing the balance of electrolytes in the body, including the heart. How can a molecule like lidocaine interfere with the function of a protein that selectively guides a small cation like Na+?  Let's find out.First of all let's look at the chemical properties of lidocaine. As indicated in the title of the post, one of the names given to the drug is xylocaine, which provides a clue to the origins of this type of compound. Chemists from the Victorian (and Wilhelmian) era were forever "brewing up" wood and coal, and extracting organic molecules. One such molecule from wood tar, was xylene (xylon is Greek for wood; ligno is incidentally Latin for wood: you know scientists are such classical scholars). The aromatic moiety of lidocaine comprises xylene: a benzene ring substituted with two methyl groups. This is linked to a short chain comprising hydrogen bond donors and acceptors of the acetamido- class (the red and blue atoms at the top LHS). For a comprehensive set of data and links to lidocaine, aspiring medicinal chemists should look at the PubChem site, which is an extraordinary resource. There are two biological targets for lidocaine: a group of fast, voltage-gated
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.