Isomerism as a drug degradation pathway and chiral drug formation

1. Introduction

Process of drug degradation where a drug gets converted into its optical or geometric Isomers is known to be isomerization. Stereoisomers are isomeric pair with identical atomic and molecular formula but different three-dimensional arrangement. For pharmaceutical aspect, the stereoisomeric pairs of greatest interest are those with one or more asymmetric (chiral) centers whose enantiomers (individual stereoisomers) are mirror images. Enantiomers are stereoisomerisms which are mirror images of each other but not superimposable, as one’s left and right hands, that are the same except for opposite orientation. Formed isomeric products often vary in their therapeutic and other pharmacological and toxicological aspects asymmetric (chiral) carbon within an organic compound gives two non-superimposable structures which are mirror images of each other hence commonly called enantiomorphs. Enantiopure compounds implies to samples having, within the limits of detection, molecules of only one chirality.

1. Pharmacological prospects of Isomerism

Stereoisomerism may be one of the responsive reasons towards different pharmacokinetic and pharmacodynamic properties within drug molecule. Pharmacokinetic differences resulting out of stereoisomerism can be witnessed in absorption of L-Methotrexate seemingly better than D-Methotrexate, Esomeprazole being more bioavailable than racemic omeprazole. Polarization is an effective process to separate two enantiomers. Human body act as an amazing chiral selector and has an ability to react against each pair of racemic drug separately therefore shows different metabolism and drug degradation pathways to show different pharmacological action of racemic drugs. Therefore, chances prevail that one isomer could turn out be an efficient and effect drug and the other one can be responsive towards various toxic effects. Barbiturates show another trend in their pharmacological properties. (+) Barbiturates may show CNS excitation while (-) Barbiturates show sedative effects where pentobarbital is a class of barbiturates with (-) pentobarbital as a potent sedative than (+) pentobarbital with side effect of hyperirritability (hiccups and involuntary twitching) and a higher degree of confusion during recovery. Optical isomers of 1-methy1-5-pheny1-5-propyl-barbituric acid (MPPB) was observed in rats. Analytical observations showed that R (-) MPPB acted as depressant, producing a dose-related loss of righting reflex with no observable convulsant activity. In contrast, the S (+) isomer produced dose- related tonic and clonic convulsions but exhibited no observable hypnotic activity. This analysis suggested that depressant and convulsant optical isomers produces behavioral effects by acting at anticonvulsant and convulsant active sites, respectively of a macromolecular complex composed of drug respective receptors. verapamil, nicardipine, nimodipine, nisoldipine, felodipine, mandipine are some of the drugs being used as calcium channel blocker when used in their  racemic form but diltiazem is a drug within this class which is a diastereomer with two enantiomers with S(-)-verapamil 10-20 times more potent than its R(+) form. Verapamil is also being used for cancer therapy for treating multidrug resistance with R (+) Verapamil with less cardiotoxicity than S (-) Verapamil. Therefore, the R-enantiomer of Verapamil can be used as a treatment against multidrug resistance during cancer therapy. Albuterol (salbutamol), salmeterol and terbutaline are bronchodilators being used for the treatment of asthma and sympathomimetic drug-selective β₂-adrenoceptor agonists being used as racemate. Pharmacologically R (-)-isomeric form of these racemate are effective and the other S (+)-isomer may be responsible for the occasional unpleasant side-effects associated with the drug. The Food and Drug Administration recently approved a chiral switch of pure l-isomer of albuterol as a preservative-free nebulizer solution. However, some clinical studies recently reported that it is neither safer nor more effective than a same dose of racemic albuterol. In contrast, levalbuterol may cost as much as 5 times more than its racemate. In neurology and psychiatry, many pharmaceuticals used are chiral compounds and most of them are marketed as racemates. Hypnotics such as hexobarbital, secobarbital, mephobarbital, pentobarbital, thiopental, thiohexital are racemic compounds and overall, only l-isomer is hypnotic or sedative, the other is either inactive or excitative. For example, S (-)-secobarbital is more potent as anesthetics compared to R (+)-secobarbital i.e. it induces an effortless and more rapid anesthetic effect. Ketamine is an intravenous anesthetic. The (+)-isomer is more compelling and less toxic than its (-)-antipode, but regrettably, ketamine is still used as a racemic drug. Isoflurane is an inhalational general anesthetic widely used in surgical operations as a racemic mixture of its two optical isomers. The (+) isomer of isoflurane is more efficient than the (-) isomer in inhibition of the currents induced by the bath application of acetylcholine. In the treatment of depression, S (+)-citalopram is over 100-fold more potent as a selective serotonin reuptake inhibitor than R (-)-enantiomer.

3. Racemic mixtures with better therapeutic approach

All racemic mixtures do not come up with toxicity and less potency which needs to separate the effective and toxic isomers through different procedures. Tramadol also renounced as Ultram, an effective in treating moderate to moderately severe pain is an opioid pain medication. The onset of pain relief usually occurs within about an hour after the administration of immediate release oral formulation. Mechanism of action is generally by binding to the μ-opioid receptor or inhibiting the reuptake of serotonin and norepinephrine. The process of synthesis leads to the formation of racemate (1:1 mixture) of (1R, 2R)-isomer and the (1S, 2S)-isomer as the main products. Some minor products of (1R, 2S)-isomer and the (1S, 2R)-isomer are also formed which are removed from the mixture through process of recrystallization formed as well. Tramadol a known drug is a racemate of the hydrochlorides of the (1R, 2R)-(+) – and the (1S,2S)-(–)-enantiomers. The resolution of the racemate [(1R, 2R) – (+)-isomer / (1S, 2S)-(–)-isomer] was done using mandelic acid. For Industrial application, tramadol is used as a racemate, despite known different physiological effects of the (1R, 2R) – and (1S, 2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals and in humans.