Celexa vs. Lexapro; right-hand vs. left-hand molecules; what does that mean?

I’m currently taking a perscription of Celexa for an anxiety disorder. In my last visit with my perscribing phsyician, he asked me to consider switching to Lexapro. Apparently, it’s a similar drug, but you can take a lower dose and get the same effectiveness. We didn’t make the switch, but we may next time. I’ve got to consider it before our next meeting.

The idea of taking a lower dose is intriguing to me, but I’m a bit confused about the explanation. I’m hoping someone with more than my 2 years of high school chemistry can help me out.

The way my physician explained it, one of these drugs is a right-hand version of the molecule and the other is the left-hand. That means nothing to me–all I remember from chemistry is the periodic table!

So what are these right- and left-handed molecules? And why would it make a difference in their effectiveness?

Right- and left-handed molecules are mirror images of each other. They interact differently with other molecules because they have different shapes, even though their atomic composition and basic configuration is the same.

Here’s a page on the Scientific American site that briefly explains the concept, with an illustration.

I’m sure some chemist will be along shortly to go into more detail.

Celexa’s active ingredient is citalopram. There are 2 forms of citalopram, the S -isomer and L -isomer. The letters stand for Sin (left) and Levo (right) rotatory form. Basically, if you draw out a chemical representation of L -citalopram and then put a mirror in front of it, you will see S -citalopram. Celexa is a combination of both of these isomers, something called a racemic mixture. The S -isomer of citalopram is actually the only isomer that is effective. Lexapro is escitalopram (S - citalopram) - it only contains the effective half. That is why you can take a lower dose and still get the same effect.

d and l stand for dextrorotary and levorotary respectively.
R and S stand for rectus (right) and sinister (left) handed molecules.
Since d and l depend on the direction of rotation of polarized light, while R and S refer back to a chemical with a defined geometric handedness, it’s possible to have chemicals which are d,R d,S l,R and l,S.

IIRC my organic chemistry, cis and trans are also terms for R and L handed. And that is where we get the term trans-fat from.

(again IIRC - it’s been some time)

Cis and trans refer to the geometry of a double bond between two atoms. Most commonly it refers to a double bond between two carbon atoms. Cis means the substituents on the carbons are on the same side, trans refers to the two substituents on opposite sides:

\
= =
\ /
trans cis (crude ASCII representation)

This is distinct from R and S, which refer to the spatial arrangement around an atom with four substituents. Most commonly this refers to carbon atoms with four substituents, and the carbon atom does not have a double bond.

Trans unsaturated fats are bad for you because (according to my physician friends) your body’s enzymes can process cis unsaturated fats (produced in nature), but cannot process trans unsaturated fats (not found in nature). Trans fats thus “gum up” the works.

If kspharm’s info is correct (that the drug you’re taking now is a racemic mixture) then IMO you should definitely make the switch. There’s no point in ingesting a chemical that doesn’t do anything for you, which is what the R isomer is.

kanicbird, close. Cis and trans are not exactly the same as R & S. R & S are for chiral centers, where the central molecule is attached to 4 different groups. Cis and trans are for olefins (carbon-carbon double bonds). Both conventions help us differentiate between two arrangements of atoms.

On preview, I see chibby’s got you covered. vBulletin doesn’t like ASCII art, apparently.

Cis and trans refer to orientation around a double bond. Cis and trans isomers will have different physical properties (such as density, melting point, etc.), whereas d and l (optical isomers) have identical (well, damn, near, anyway) physical properties.

The best way to describe how this “chirality” works is to look at your hands. They are (well, they should be) mirror images of each other; each has a thumb which is opposed to the other four fingers. So what’s the big whoop? Try to shake someone’s left hand with your right one; It’s pretty clumsy. In nature, many of the enzymes that regulate and enable all of the chemical reactions that keep us upright and breathing experience something similar. Given two molecules which are mirror images of each other, the enzyme will process one molecule, but not the other.

Fortunately, mother nature excells at making such molecules. For example, plants and animals make amino acids almost exclusively in the d orientation.

Synthetic chemists, on the other hand, with their test tubes and beakers, tend to end up with mixed results. When synthesizing an optically active molecule, you usually end up with a 50-50 mixture of both forms. This means that 50% of the drug you just spent the last month making is worthless, meaning that you have to take twice as much to get the same active dose.

So very often, the drug manufacturer has a choice:

1. Make a drug through a synthetic route which only yields 50% of the preferred isomer, and sell it.
2. Same as above, but somehow separate the inactive isomer and sell the active one.
3. Develop a synthetic route which produces only the isomer of interest.

In the case of option 1, when applying to get a new drug approved, if you have a mixture of two isomers, you are in fact applying for * two* drugs, and have to demostrate the safety of the inactive isomer (usually, the inactive isomer is just that-inactive and benign- but this is not always the case; one isomer of Ethambutol is active in fighting tuberculosis, while its isomer can cause optical neuritis and blindness).

Option 2 is often taken, but separation of optical isomers isn’t always easy, especially on a large scale, adding to the cost of manufacturing the drug.

Option 3 is the most elegant approach, but typically requires many more synthetic steps and more expensive precursors (ingredients), again adding to the cost of production.

In your specific example, it may be that your current medication consists of a mixture of active and inactive isomers (option 1) , while the lower-dose medication consists solely of the active isomer (option 2 or 3), which is why I’m gonna guess that the latter, while less hassle, is probably gonna be more costly.

Cha-ching!!!

Did a little googling before I hit the sack and found this:

So Celexa is the mixture of isomers while Lexapro is a single isomer.

bizzwire: Another option is to market the racemic mixture only until the patent covering it is about to run out, file a new patent on just the active S isomer, and market that exclusively for the next decade.

While you’re correct that there’s point in ingesting a chemical that doesn’t do anything for you, it’s not a slam-dunk argument that the “inactive” isomer of citalopram, or any chiral drug for that matter, “doesn’t do anything for you.”
The uptake, partitioning within the body, metabolism, and action of drugs is a hideously complex process. Depending on the drug, an “inactive” isomer may act to, for example, fill dead end tight-binding sites on blood globulins, or overload the cytochrome system normally responsible for oxidizing the active species, or any of dozens of other possibilities. Each of these effects can, and frequently does, effect the pharmacokinetics, rates of adverse reactions, and overall clinical efficacy of a drug.

Thalidomide is another drug where chirality came into play. One version of the molecule is a morning-sickness drug, the other causes severe birth defects.

Thalidomide is the classical example of why using an enantiomerically pure drug instead of a racemic mixture is a good idea. There are now several drugs which were once sold as racemates that are available as single enantiomers. Nexxium™ (esomeprazole) is the S isomer of Prilosec™ (omeprazole). I think there’s enantiomerically pure Prozac also. Some drugs, like Paxil, have always been sold as a single isomer.

Organic synthesis has reached a point where preparing single enantiomers is practical and efficient for most drugs. Though research into new “asymmetric” reactions is ongoing and is a major area of organic chemistry, it’s no longer appreciably more difficult to produce a single enantiomer of a drug than to produce the racemate. Thus, these “new” drugs that are really just one enantiomer of an old racemic drug are primarily a marketing ploy.
So, while nature is still better at asymmetric synthesis than organic chemists are (mostly because enzymes are inherently asymmetric catalysts for a specific reaction), we’re getting pretty good at it.

On stereochemical nomenclature:
The labels d, l, dl- for dextrorotatory, levorotatory and racemic compounds are obsolete; the preferred system is (+),(-),(±)-. This avoids confusion with the labels D, L, DL-, which refer to the orientation of a certain group on the right or left side of a molecule when drawn as a Fischer projection (an old, annoying way of drawing molecules, mostly carbohydrates; DL- means a mixture of D- and L- compounds). Since D, L, DL- is closer akin to R, S- than to d,l-, it’s a good idea to use the new labels.

R,S nomenclature depends on the ‘priority’ of groups attached to a carbon atom according to a system called the Cahn-Ingold-Prelog rules. This is the preferred method of describing stereochemistry. Cis,trans- isomerism has already been described, but this really only applies to double bonds with two different substituents. If more than two non-hydrogen groups are attached to the double bond, E,Z- nomenclature is used. This uses the same Cahn-Ingold-Prelog rules as R,S-. If the two groups having the highest priority are on the same side of the double bond (i.e., a cis-like configuration), then it’s Z, from the German zusammen meaning “together”. If they’re on opposite sides (trans-like), then it’s E, for entgegen “opposite”.

The profoundly confusing world of stereochemical nomenclature isn’t limited to these (but those are most of the types of isomerism found in organic molecules). There’s also re, si-, mer, fac-, delta, lambda-, syn,anti-…

If you want to learn very slightly more about chirality while having an altogether insignificant amount of fun, you should play the Chirality Game at the Nobel website.

I love the part where a snail explains the meaning of “chiral” to another snail:

Look at this molecule. It is non-superposable on its mirror image.

That’s the definition of “enantiomer”; really helpful, isn’t it?

IIRC, doesn’t thalidomide racemize under physiological conditions, so that administration of the enantiomerically pure molecule leads to the racemate? Thalidomide is making somewhat of a comeback, and is looking promising for multiple myeloma treatment.

I hadn’t heard about thalidomide racemization before, but I knew that even with the single enantiomer, patients were required to sign waivers and pledge to use multiple methods of contraception to avoid pregnancy.

Anyone who knows enough ochem to care about the mechanism should be able to figure it out easily on seeing the structure, which would tautomerize and racemize under physiological conditions. Hydrolysis of the amides is also possible. Here’s the structure: http://www.chem.yale.edu/~chem125/125/thalidomide/struc.gif

Alkylating the chiral center of thalidomide prevents racemization, but it must reduce pharmacological activity.

Wow. This is really interesting and helpful! You guys are awesome. I hadn’t thought that molecules were 3-dimensional. Now the “mirror image” thing makes much more sense.

Gee, maybe I should have taken o-chem back in high school. This stuff isn’t nearly as dry and useless as I thought.

A good example of this is olestra. The easiest way to make a fat your body doesn’t absorb is too merely change the “handedness” of an existing fat.

Fats are strange. Fatty acids themselves, CH3-(CH2)n-COOH, are achiral. Glycerol, CH2(OH)-CH(OH)-CH2(OH), is prochiral, meaning that it is not chiral, but could be made chiral by changing one part of the molecule (e.g. the OH groups at the end). Fats are esters of glycerol with three fatty acids. So the components of fat are achiral, but fats are chiral because the enzymes that make them are capable of making chiral molecules out of achiral and prochiral ones. The enantiomer of the usual fats (the opposite ‘handedness’) might well be absorbed anyway though, because esters are easily broken down by acid or base, and the conditions of the digestive system should be enough to at least partially break them down without enzymes.

Olestra would seem to be a nightmare for dieters. Like fats, Olestra is an ester of fatty acids with an alcohol. But unlike ordinary fats, Olestra is an ester of fatty acids not with innocent glycerol, but with sugar. To make Olestra, six, seven or eight fatty acids (generally stearic acid, a saturated fat) are attached to a molecule of sucrose.

But Olestra can’t be metabolized, because the molecule (with 6, 7 or 8 fatty acids attached to an alcohol much larger than glycerol) is too large to be absorbed or metabolized. It simply won’t fit in the enzymes that break down fat. It supposedly tastes like ordinary fat, but has no nutritive value since it just passes through the body (though sometimes with rather undesirable consequences).

MaddyStrut: This is about as interesting as ochem gets. =) A lot of ochem has very interesting and practical applications, but the process of learning it involves a lot of things that are not interesting. There’s a lot of memorization, and a lot of theory you have to understand. It’s not really dry or useless – but learning it well isn’t really all that fun either. Of course, that doesn’t mean you can’t learn some of the more interesting parts without having to go through the traditional process.