Enantiomers their importance in psychopharmacology Introduction

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The majority of naturally occurring drugs and biologically active compounds are asymmetrical in their chemical structure. This means that the molecule is structured around one or more carbon atoms in such a way that the molecule is distributed mostly on the right (R=rectus) or left (S=sinister) of the symmetrical carbon atom, the so-called chiral centre of the molecule. Thus a large proportion of psychotropic drugs in current use possess one or more chiral centres and therefore exist in pairs of enantiomers which differ in terms of their three-dimensional structures. However, it must be remembered that chirality can apply not only to molecules but also to anatomical structures. For example, the left and right hands are chiral structures as is evident when one attempts to put a left-handed glove on the right hand and vice versa!

At the cellular level, the various types of receptor, transporter, enzyme and ion channel are all chiral in form. Thus although the enantiomers of a drug may have identical physicochemical properties, the way in which they may interact with chiral targets at the level of the cell will give rise to different pharmacodynamic and pharmacokinetic properties. A few simple examples will illustrate how taste and olfactory receptors can differentiate between enantiomers. Thus R-carvone tastes like spearmint whereas the S-isomer tastes like caraway. Similarly, R-limolene smells like lemon whereas the S-enantiomer tastes of orange.

In psychopharmacology, interest in the properties of enantiomers has been aided by the need to improve the therapeutic efficacy and decrease the side effects and toxicity of drugs. For example, if the therapeutic activity resides entirely in one enantiomer (called a eutomer) then giving a racemic mixture which contains the active and the inactive enantiomer is clearly wasteful. Thus using the single enantiomer (isomer or eutomer) should enable the dose of the drug to be lowered, reduce the interpatient variability in the response and, hopefully, reduce the side effects and toxicity of the drug (see Table 3.4).

Table 3.4. Possible advantages of the single stereoisomer over the racemic mixture

1. Reduction in the therapeutic dose.

2. Reduction in the interpatient variability in metabolism and in response to treatment.

3. Simplification of the relationship between the dose and the response to treatment.

4. Reduction in the toxicity and side effects due to the greater specificity of action of the isomer with the relevant biological processes.

In addition to the possible advantages of the single enantiomer, the pharmacologically inactive enantiomer may reduce the efficacy of the active isomer by reducing its activity at its site of action or by interfering with its metabolism. Thus separating a racemic mixture into its enantiomers, and assessing the individual properties of the isomers would seem to be a reasonable approach to improving the clinical profile of many well-established psychotropic drugs. The process whereby a racemic mixture is reintroduced as a single enantiomer is termed ''chiral switching''.

While there appears to be a compelling argument for using single enantiomers whenever possible in order to improve the efficacy and safety of a racemic drug, there is no certainty that chiral switching will always be beneficial. For example, in 1979 seven cases of inadvertent injection of the local anaesthetic racemic bupivacaine resulted in cardiovascular collapse in a few patients. The toxicity appeared to reside entirely in the R-isomer so that, by chiral switching, a safer and less toxic local anaesthetic was produced. Other examples have not been so successful however. For example, the chiral switching of racemic fenfluramine to its R-enantiomer, dexfenfluramine (the nomenclature has changed recently so that D-enantiomers, Dex enantiomers, are now termed R-enantiomers while the L-enantiomers, levoenantiomers, become S-enantiomers) was at first heralded as a successful new appetite suppressant. However, it was soon shown that, despite its improved efficacy, the R-enantiomer was more likely to cause pulmonary hypertension. This has resulted in the withdrawal of the drug.

Some examples of the properties of single enantiomers in psychopharmacology

(1) Analgesics - methadone

This synthetic opiate was introduced in 1965 to manage opioid dependence and has been successfully used as an aid to abstinence since that time. Methadone is a racemate, the R-enantiomer being the pharmacologically active form of the drug. This isomer shows a 10-fold higher affinity for the mu and delta opioid receptors, and nearly 50 times the antinociceptive activity of the S-enantiomer. In addition, the R-isomer is less plasma protein bound than the S-form; the latter isomer being more tightly bound to alpha-1 acid glycoprotein. The plasma clearance of the R-form is slower than the S-isomer. Patients treated with the isomers of methadone showed considerable individual variability, with some parameters reaching 70%: this would not have been detected if the racemate had been administered. These pharmacokinetic differences could be crucially important when patients are being treated with methadone as part of an opiate withdrawal programme as relatively small decreases in the plasma concentration could produce marked changes in mood, thereby undermining the positive benefit of the methadone withdrawal programme.

(2) Sedative/hypnotics - zopiclone

Zopiclone is widely used as a sedative-hypnotic. It is metabolized to an inactive N-desmethylated derivative and an active N-oxide compound, both of which contain chiral centres. S-Zopiclone has a 50-fold higher affinity for the benzodiazepine receptor site than the R-enantiomer. This could be therapeutically important, particularly if the formation and the urinary excretion of the active metabolite benefits the S-isomer, which appears to be the case. As the half-life of the R-enantiomer is longer than that of the S-form, it would seem advantageous to use the R-isomer in order to avoid the possibility of daytime sedation and hangover effects which commonly occur with long-acting benzodiazepine receptor agonists.

(3) Neuroleptics - thioridazine

Thioridazine is a complex first-generation antipsychotic agent that is metabolized to two other pharmacologically active drugs (mesoridazine and sulphoridazine) which have been introduced as neuroleptics in their own right. All three neuroleptics have chiral centres. Interest in thioridazine has arisen in recent years because of the higher incidence in sudden death, due to cardiotoxicity, found in patients who had been prescribed the drug. Thioridazine-5-sulphoxide would appear to be the metabolite responsible for the cardiotoxicity. This metabolite alone has four chiral centres and knowledge is lacking concerning the toxicity of these enantiomers which serves to illustrate the complexity of the problem.

Regarding the pharmacological activity of thioridazine, the R-enantiomer has been shown to be at least three times more potent than the R-isomer in binding to the D2 dopamine receptors and nearly five times more potent than an alpha-1 receptor antagonist. Conversely, the S-isomer has a 10-fold greater affinity for the D1 receptor than the R-form. Thus the pharmacological consequences of using a single enantiomer of thioridazine are, unlike the other three examples given, very complex. Thus if the S-enantiomer was selected, while the potency would undoubtedly increase (due to its D2 antagonism), the chances of postural hypotension (due to the alpha-1 receptor antagonism) would also be greater. Furthermore, the relative activity and toxicity of the individual enantiomers and their metabolites is unknown. With regard to the extrapyramidal side effects for example, experimental studies have shown that the R-isomer is more likely to cause catalepsy and is, in addition, far more toxic than the S-form. Dose-response relationships have also been undertaken on the individual enantiomers versus the racemate form of thioridazine and show that the racemate is 12 times more potent than the S-isomer and three times more potent than the R-isomer.

(4) Antidepressants

It is widely agreed that there is little difference in the therapeutic efficacy between any of the first- and second-generation antidepressants. However, in terms of their tolerability and safety, the second-generation drugs are superior. Of these, the SSRI antidepressants are the most widely used but, despite their clear advantages over the tricyclic antidepressants which they have largely replaced in industrialized countries, they have such side effects as nausea and sexual dysfunction which can affect compliance. While there are clearly differences in the frequency of side effects between the SSRIs, no clear overall advantage emerges for any one of the drugs.

Many currently used antidepressants are chiral drugs (for example, tricyclic antidepressants, mianserin, mirtazepine, venlafaxine, reboxetine, fluoxetine, paroxetine, sertraline, citalopram), some of which are administered as racemates (such as the tricyclics, mianserin, mirtazepine, fluoxetine, reboxetine, venlafaxine, citalopram) while others are given as single isomers (paroxetine and sertraline).

The relative benefits of the enantiomers of antidepressants vary greatly. For example, when the therapeutic properties of the enantiomers are complementary (for example, mianserin) then use of the racemate is an advantage. However, if there are qualitative, but not quantitative, similarities then it would be beneficial to develop the active isomer. This has recently occurred with the development of citalopram.

The S-enantiomer of citalopram (escitalopram) is over 100 times more potent in inhibiting the reuptake of 5-HT into brain slices than the R-form and is devoid of any activity at the neurotransmitter of other receptor types (racemic citalopram has an affinity for histamine receptors and causes sedation). In in vivo studies, escitalopram is more potent than the R-form or the racemate in releasing 5-HT in the cortex of conscious rats; it has been shown to have antidepressant and anti-anxiety properties in both animal models and in patients. With regard to its side effects, the frequency of nausea and ejaculatory dysfunction after escitalopram is approximately the same as that of the racemate. From the results of the published clinical studies, it would appear that the tolerability of escitalopram is slightly better than the racemate and the time of onset of the clinical response may be slightly faster but this needs confirmation. In general, the adverse effects were mild and transient with a low patient withdrawal rate. Early clinical trials suggest that escitalopram is as effective as citalopram in the treatment of depression and anxiety disorders.

In CONCLUSION, current evidence suggests that for many psychotropic drugs there are functional differences between the enantiomers and the racemate which could have important clinical implications. However, it is apparent that the possible advantages of developing a single enantiomer must be considered on a drug-by-drug basis. For example, fluoxetine, like most SSRIs, exists in a chiral form but the most active enantiomer found in experimental studies caused cardiotoxicity in some patients. In general, however, it would appear that knowledge of the stereochemistry of psychotropic drugs will help in the development of new, and hopefully more effective, molecules in the near future.

Drug-protein interactions

In addition to metabolic interactions, consideration should be given to drug-protein binding interactions, although there is little clinical evidence to suggest that such interactions are of any consequence with the SSRIs. It must be stressed that many liver enzymes are non-specific for their substrates and that most drugs are metabolized by multiple pathways. Good therapeutic practice demands that drug interactions should be considered carefully, particularly in subpopulations of depressed patients such as the elderly or those with hepatic dysfunction or a history of alcoholism.

In SUMMARY, it would appear that a detailed knowledge of the pharmacokinetics of the main groups of psychotropic drugs is only of very limited clinical use. This is due to limitations in the methods for the detection of some drugs (e.g. the neuroleptics), the presence of active metabolites which make an important contribution to the therapeutic effect, particularly after chronic administration (e.g. many antidepressants, neuroleptics and anxiolytics), and the lack of a direct correlation between the plasma concentration of the drug and its therapeutic effect. Perhaps the only real advances will be made in this area with the development of brain imaging techniques whereby the concentrations of the active drug in the brain of the patient may be directly measured. Until such time as the kinetics of psychotropic drugs in the brain can be properly assessed, it can be concluded that the routine determination of plasma levels of psychotropic drugs is of very limited value.

Despite the limited value of measuring plasma psychotropic drug concentrations to assess clinical response, a knowledge of the pharmaco-kinetics of such a drug can be of value in predicting drug interactions.

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