Isomerism as a drug degradation pathway and chiral drug formation 1. IntroductionProcess 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.Pharmacological prospects of IsomerismStereoisomerism 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 ?2-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 approachAll 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 ?-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.            Fig1. Different stereoisomeric structure of Tramadol as an analgesic drug4. Toxicology related to chiral drug moleculesLarge pharmacodynamic and pharmacokinetic differences between isomeric groups may show significant stereo selective toxicity which can be present in either one or both isomeric groups with pair of enantiomers having same or different trends of toxicology. Chances prevail that they can be located in the active or inactive part of the enantiomer. Therefore, many available drugs presently being marketed are available in single isomeric form which is all because of their related toxicity. Dopa or dihydroxy-3, 4 phenylalanine is the known precursor of dopamine used for the treatment of Parkinson disease. Initially it was used as a racemic form of D, L- dopa, but the racemic mixture showed toxicity like agranulocytosis of d-isomer, therefore, only levorotary form called L-Dopa is actually used in therapeutics. There are number of chiral drugs being used in their racemic form because of may be difficulty in separation or high cost purification.R (-)-ketamine (distomer) is responsible for agitation, hallucination, restlessness but these actions are seen with S (+)-ketamine (eutomer). Secobarbital enantiomers are equipotent as anticonvulsants, but the S(-)-isomer is a more potent anesthetic and is also more toxic than the R(+)-isomer .In the case of cyclophosphamide, its two isomers exert the same toxicity .For thalidomide, theoretically, only the inactive S(-)-isomer is teratogenic, but practically, both isomers are genotoxic because of its in vivo interconversion and of its species-dependence .Examination with mice specimen conducted  in 1961 suggested that only one enantiomer was teratogenic while the other possessed therapeutic activity. On contrary, subsequent test with rabbits showed teratogenicity in both the enantiomers. The S-isomer (in contrast to the R-isomer) can be linked to thalidomide’s teratogenic effects .However, attempts to formulate the R-isomer have not solved the problem of teratogenicity, as the two isomers are readily interconvertible in vivo. Moreover, the cause of toxicity of thalidomide could be due to its numerous chiral and achiral metabolites of which pharmacological and toxicological studies remain very scarce.5.Effect of Chiral drug on Pharmacokinetic and Metabolic processResponse of drug on the absorption, distribution, metabolism and elimination is the most important pharmacokinetic consideration. Stereo-pharmacokinetic studies and stereoselective drug assays are the important consideration. The potential for discrimination between enantiomers at each of these stages is therefore important and emphasizes the need for stereo-pharmacokinetic studies and stereospecific drug assays. Clinical studies of various stereo isomeric drugs have shown various pharmacokinetic and pharmacodynamics differences within isomeric group. For example, the pharmacokinetic aspects for considering antiarrhythmic drugs, absorption of these drug is a problem which is due to stereo selectivity but distribution, metabolism and excretion is significantly achieved by one of the available enantiomer. Plasma protein binding is stereo-selective for most of these drugs in terms of distribution, which results in up to two-fold differences between the enantiomers in their unbound fractions in plasma and volume of distribution. These drug as metabolized by the hepatic system of body. Additionally, different drug isomers response towards different stereo selectivity towards complete drug metabolism and degradation. Therefore, isomeric drugs wide pathways involved in there metabolic degradation. These effects provide us information regarding the drug plasma concentration which gives us great clinical relevance of the drug and its therapeutic efficiency. Stoschitzky et al brought forward many differences, The dose administration path play a great role where IV dosing gives the maximum drug input than any other mode of administration. There are marked pharmacokinetic differences between the d- and l-enantiomers of most ?-blockers, in particular under exercise and when extensive and poor metabolizers are compared.  When the racemic mixture is administered orally or intravenously Plasma concentrations of d and l-enantiomers usually differ axiomatically and in wide ranges .Therefore in a broad approach factors like drug dosing rate or the interaction of drug isomers may affect the selectivity and PK, PD of drug ligands. Described in a different study  the pharmacokinetic profile of propranolol enantiomers and their enantiomer sulfate and glucuronide metabolites, in human urine and serum showed that the S/R ratios of mother molecule in serum and urine were about 1.4, of sulfate conjugate about 2 and of major glucuronide metabolite about 3. But variation of the ratios S (-) – active/R (+)-inactive isomers between them was also observed.6. ENANTIOSELECTIVE ANTIBODIES TO CHIRAL DRUGSHuman immune system is quiet sensitive towards foreign products therefore as drug isomers are chosen to be organ specific therefore the organ will easily identify isomer of choice which in return will produce enantiomer specific antibody which can detect any kind of structure change within the drug product. According to Sahui-Gnassi et al.  And Chikki-Chorfi et al.  The maintenance of carbon asymmetry is of great importance so as to obtain antibody specific to chiral drug. In another aspect, these enantioselective antibodies have been profitably used to separate enantiomers e.g. antibodies to propranolol enantiomers methadone enantiomers amphetamine enantiomers warfarin enantiomers  etc. Also they are still scarce in comparison with numerous antibodies to achiral drugs. The application of enantioselective antibodies to chiral drugs plays a significant role in biochemistry. Their application  as specific reagent is not only limited to immunoassays such as radioimmunoassay  enzymatic immunoassay but also for histologic immunoassay, immunoaffinity chromatography, immunoextraction of chiral drugs, liquid chromatography using antibodies as chiral selectors, etc. These immunoassays can be extensively used in pharmacokinetics, drug therapeutic monitoring, toxicological diagnostic, drug pharmacological assessment, identification of drug fixed on target organ, etc. 7. DISCUSSIONTo over the problem of drug expiry and drug degradation, pharmaceutical companies are utilizing the use of a single drug isomer more than the use of drug racemic mixtures which claims for more of drug efficacy and activity with decrease in stereo selective toxicity. Racemic Drug mixture often contain an inactive and an active form among which chances prevail that one could be toxic and another with significant therapeutic effect therefore roper separation techniques are required to get the drug of choice and avoid the problems of stereoselectivity.Chiral separation of drug is most of the time an important step to maintain drug selectivity and therapeutic activity because the clinical assessments have shown racemic drugs to have several drawback which are unsuitable for its use as a therapeutic entity. But, some racemate do show an advantage over single isomer or the separation process is quite expensive therefore racemic drugs are used in a whole approach.1. Chhabra, N., M.L. Aseri, and D. Padmanabhan, A review of drug isomerism and its significance. International journal of applied & basic medical research, 2013. 3(1): p. 16-18.2. F. Corno Md, F.F.A., Isomerism. 2004. p. 181-193.3. Landoni, M.F. and A. Soraci, Pharmacology of chiral compounds: 2-arylpropionic acid derivatives. Curr Drug Metab, 2001. 2(1): p. 37-51.4. Ariens, E.J., Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology. Eur J Clin Pharmacol, 1984. 26(6): p. 663-8.5. Patocka, J. and D. Ales, Biomedical aspects of chiral molecules. Vol. 2. 2004.6. Asmus, M.J. and L. Hendeles, Levalbuterol nebulizer solution: is it worth five times the cost of albuterol? Pharmacotherapy, 2000. 20(2): p. 123-9.7. Shouip, H., Tramadol synthesis and mechanism of action. 2015.8. Jamali, F., R. Mehvar, and F.M. Pasutto, Enantioselective Aspects of Drug Action and Disposition: Therapeutic Pitfalls. Journal of Pharmaceutical Sciences, 1989. 78(9): p. 695-715.9. Scott, A.K., Stereoisomers and drug toxicity. The value of single stereoisomer therapy. Drug Saf, 1993. 8(2): p. 149-59.10. Eichelbaum, M., Side effects and toxic reactions of chiral drugs: a clinical perspective. Arch Toxicol Suppl, 1995. 17: p. 514-21.11. Mehvar, R., D.R. Brocks, and M. Vakily, Impact of stereoselectivity on the pharmacokinetics and pharmacodynamics of antiarrhythmic drugs. Clin Pharmacokinet, 2002. 41(8): p. 533-58.