Stereochemistry

This *should* be a real quickie, given that it draws on concepts I've talked about before (namely chirality and structure-activity relationships). (Strangely, I don't have a post entirely on chirality- probably a good post would involve diagrams which I'm too lazy to draw- but that post I just linked to, as well as this post on carbohydrates, cover a fair bit.)

1) Define the terms “stereoisomer” & “chiral centre"

Ehhhh can't be bothered typing, read this post on carbohydrates instead.

2) Demonstrate a basic appreciation of the drawing conventions used to denote the presence of a chiral carbon within drug structures

In diagrams, you might have seen dashed lines and/or wedges between atoms. Dashed lines indicate that the atom in question is going "into" the page (i.e. away from you) while wedges indicate the opposite- that the atom in question is coming "out of" the page. You can use these to help you work out how the atoms are oriented, and from that you can work out which enantiomer they are. In racemic mixtures (i.e. mixtures with both enantiomers in equal quantities), a squiggly line might be drawn instead.

3) Show an appreciation of the pharmacodynamic implications of stereoisomerism, using the “3 contact point model” to explain such phenomena

Stereoisomers have different shapes, which means that they have different affinities for different targets. Can't be bothered drawing models or anything, unless anyone really wants me to.

4) Show an appreciation of the pharmacokinetic implications of stereoisomerism in drugs, especially during drug metabolism.

Once again, different stereoisomers have different affinities for different targets. Not only does this affect how well a drug binds to its target, but it may also affect absorption because certain stereoisomers may have greater affinities for certain transport proteins. (Note that chirality only affects "active" processes such as active transport- it doesn't affect a drug's ability to diffuse across the membrane.)

Another important point of note is that sometimes metabolism affects stereoisomerism. Metabolism can change a drug from one stereoisomer to another, abolish chirality or establish new sites of chirality. These all have implications for how a drug acts in the body.

5) Be able to define the term “chiral switching” and give examples of the use of this strategy.

"Chiral switching" is basically a company marketing a pure enantiomer of a drug, rather than the racemic mixture. For example, citalopram, an antidepressant drug, is a racemic mixture; escitalopram contains the S-enantiomer of citalopram only (hence escitalopram. Very funny, pharmacists). This is often done if one enantiomer is known to be much more effective than the other. Selling a drug containing only the effective stereoisomer means that only half the dose needs to be taken, while eliminating any negative effects that metabolism of the ineffective stereoisomer may have had. Going back to the escitalopram example, apparently escitalopram may be more effective than citalopram. (On an unrelated note, escitalopram is a massive pain in the rear end to go off. I'm currently tempted to stick a meme on here with my psychiatrist's face and the words "'Go off your escitalopram,' she said. 'It will be easy,' she said." But I'm nice, and I won't do that to her.)

A few quick definitions: if one enantiomer is better, then the better one is known as the eutomer while the worse one is the distomer (from the Greek "eu" meaning "good" and "dis" meaning "bad"). The ratio between the two is known as the eudismic ratio.

6) Show an appreciation of the toxicological implications of stereoisomerism

Of course, if stereoisomerism can have implications as to which targets drugs bind to, it can also have toxicological implications if the binding of one stereoisomer leads to negative effects. The no-brainer solution then is to use "chiral switching" to give patients only the stereoisomer that isn't toxic; however, this isn't always so simple as chirality may change within the body due to metabolism or otherwise.

One possible example of so-called "chiral toxicity" is ketamine. It's an anaesthetic, but it's also used as a recreational drug. It's thought that S-Ketamine has better anaesthetic activity and fewer side effects, while R-Ketamine is more likely to cause psychosis, agitation and amnesia.