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.
(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.
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