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Stereoisomers in pharmacology
- 1. STEREOISOMERS in Pharmacology - Presenter: Dr. Chandini Moderator: Dr. Padmaja Udaykumar 1
- 2. Overview Introduction Basic concepts in isomerism History Chirality & enantiomers Nomenclature system Chiral drugs in biological systems Importance of chirality in drugs Single enantiomer vs racemic mixture Conclusion 2
- 3. INTRODUCTION • Stereochemistry – deals with properties of stereoisomers / 3-D arrangement of atoms & molecules. • Clinical importance of isomerism isomers differ in their PK and PD properties. • Introduction of safer & more effective drug alternatives. 3
- 4. 4 • Isomers are molecules of identical atomic compositions (same molecular formula) • but with different bonding arrangements of atoms or orientations of their atoms in space. Basic concepts in isomerism
- 5. • 3 types – Constitutional (structural/positional) - Configurational (stereoisomers), and - Conformational. • Stereoisomers – molecules identical in atomic constitution & bonding, but differ in the 3-D arrangement of atoms. 5
- 6. History • 1827: Isomerism 1st noticed in by Friedrich Woehler: found silver cyanate identical to silver fulminate, but properties were different. • 1830: Jons Jacob Berzelius coined the term isomerism. • 1848: Louis Pasteur separated tartaric acid 2 mirror image forms (optical isomers) 6
- 7. The story of Thalidomide • Primarily a sedative/hypnotic, used to treat sickness in 1950s (Contergan) • Phocomelia • Original drug – mixture of 2 forms • R forms – therapeutically active (sedation) S forms teratogenic • Still used (rarely) – only 1 form. 7
- 8. CHIRALITY & ENANTIOMERS • Chirality - geometric property of a rigid object (molecule or drug) of not being superimposable with its mirror image. • left- and right-handedness 8
- 9. • Chiral molecule - not superimposable on its mirror image. • Molecules superimposed on their mirror images = achiral (not chiral). • "cheir" = handedness What are enantiomers ? 2 mirror images of a chiral molecule What are optical isomers? optically active enantiomers (rotate the plane of polarized light) 9
- 10. • Have same physical & chemical properties (identical melting points, pKa, solubities, etc.) • But in chiral environments (receptors & enzyme in the body) they can behave differently. • Chirality is d/t asymmetrically tetrahedral carbon atoms = ‘chiral centre’ 10
- 11. • Racemic mixture = mixture of equal portion (50:50) of + and – enantiomers, - are optically inactive. • Isomerization / enantiomerization = conversion of 1 stereo-isomeric form into another Eg. R-ibuprofen S-ibuprofen 11
- 12. • Diastereomers = molecules with >/= 2 chiral centres. - maximum no. of stereoisomers possible = 𝟐 𝒏 ( Rule of 2 𝑛 ) n = number of chiral centres Eg. Ephedrine – 2 chiral centres = 4 isomers (RR, RS, SS & SR) 12
- 13. Nomenclature System I. Based on the optical activity – 1. Dextrorotatory - Rotates plane polarized light towards right (clock-wise) ‘d’ or ‘+’ 2. Levorotatory - Rotates plane polarized light towards left (anti-clockwise) ‘l’ or ‘–’ Limitation: sign of rotation does not predict absolute configuration of atom 13
- 14. 14
- 15. II. Based on configuration 1. D / L system • Placement of group on the right or left. • Projection such that main C chain is positioned vertically • Position of principal substituent relative to C chain identified: to the right D configuration to the left L configuration. 15
- 16. • specific to sugars & amino acids. • eg Alanine Glyceraldehydes 16
- 17. 2. Cis-/ Trans-isomer • 2 similar / higher priority groups attached the carbon on the same side = Cis isomer on the opposite side = Trans isomer 17
- 18. III. Based on R and S system: • 4 grps bound to tetrahedral asymmetric C atoms, which are ranked. • Grps oriented in clockwise fashion = R isomer (‘rectus’) oriented anti-clockwise = S isomer. (‘sinister’) • eg, S- & R-Glyceraldehyde 18
- 19. • d / dextro, and l / levo, are obsolete and should be avoided. • R/S system for absolute configuration & +/− system for optical rotation should be used. 19
- 20. CHIRAL DRUGS IN BIOLOGICAL SYSTEMS • Achiral environment - enantiomers have identical physical & chemical properties • Chiral environment (living systems) - behave differently • It is appropriate to consider the 2 enantiomers of a given chiral drug as 2 separate drugs with different properties. 20
- 21. 21
- 22. IMPORTANCE OF CHIRALITY IN DRUGS • Approx 50% of marketed drugs are chiral. • The 2 enantiomers of a chiral drug may differ significantly - BA, rate of metabolism, metabolites, excretion, potency and selectivity for receptors, transporters &/or enzymes, and toxicity (PK and PD differences). 22
- 23. Examples of PK differences 1. Absorption: L methotrexate is better absorbed than D Methotrexate Esomeprazole is more bioavailable than racemic Omeprazole. 23
- 24. 2. Distribution: S-warfarin is more extensively bound to albumin than R-Warfarin lower Vd Distribution of Levocetrizine smaller than that of its dextro enantiomer – better safety & efficacy. Similarly d-propanolol is more extensively bound than l-propanolol 24
- 25. 3. Metabolism • Warfarin isomers - metabolized by different routes. • S form is more potent and is metabolized relatively faster by ring oxidation, while R form is less potent and degraded by side chain reduction. • 𝐭 𝟏/𝟐 of S-warfarin - 32 hours, R-warfarin - 54 hours. 25
- 26. Examples of PD differences 1) Pharmacological actions – Quinine - antimalarial property quinidine (d-isomer) - antiarrhythmic l sotalol - β blocking action d sotalol has antiarrhythmic action. L methorphan - potent opioid analgesic Dextromethorphan - cough suppressant. 26
- 27. S ketamine - potent anasthetics R ketamine - hallucinogenic Nebivolol - highly selectively beta-1- blocking effects, L-isomers – vasodilatation 27
- 28. 2) Therapeutic and adverse effects R thalidomide - sedative S thalidomide teratogenic effect. R-Naproxane - to treat arthralgic pain S-Naproxane teratogenic D-ethambutol - to treat TB L ethambutol blindness. 28
- 29. (S) (+)-ketamine - fewer psychotic emergence reactions, and better intraoperative amnesia, and analgesia than its R- enantiomer L-dopa - Rx for Parkinson's disease D-dopa deficiency of WBCs susceptibility to infections. Never been used. 29
- 30. 3) Efficacy S (-) carvedilol is 100 times more potent as β blocker than R (-) carvedilol. ( α receptor blocking action is equipotent) S timolol is more potent β receptor antagonist than R timolol but both reduce intra ocular tension to same extent. 30
- 31. 4) Drug interaction : 2 stereoisomers can compete for binding to the same receptor. Eg. S methadone antagonizes respiratory depressant action of R methadone. If the 2 isomers are agonist & antagonist - racemic mixture acts as partial agonist 31
- 32. Eg. Picendol (Opioid analgesic drug): (+) (3S, 4R) enantiomer - pure agonist (-) (3R, 4S) enantiomer - pure antagonist (+) (3RS, 4RS) racemic mixture - partial agonist 32
- 33. SINGLE ENANTIOMER vs RACEMIC MIXTURE •Approx 50% of chiral drugs are marketed as mixtures of enantiomers rather than single enantiomers. • it is critical to distinguish the single enantiomer from the racemic form - may differ in their dosages, efficacies, side effect profiles, or use. • Decision to choose should be made on the basis of data from clinical trials & clinical experience. 33
- 34. Advantages of single enantiomers over racemic mixtures: less complex & more selective pharmacodyanamic profile lesser adverse drug reactions improved therapeutic profile less chances of drug interactions patients are exposed to less amount of drug lesser metabolic, renal & hepatic load of drug, easier therapeutic drug monitoring 34
- 35. Examples for racemic mixtures that have been marketed – 1. Amphetamine and Dextroamphetamine 2. Bupivacane and levobupivacane 3. Ofloxacin and Levofloxacin 4. Albuterol and Levalbuterol 5. Omeprazole and Esomeprazole 6. Cetirizine and Levocetirizine 35
- 36. • A number of antidepressants are currently marketed as racemates. •Higher proportion of single enantiomers developed. 36
- 37. Drugs which are better as single enantiomers – • 1 enantiomer therapeutic effect (Eutomer) other inactive/undesirable effect (Distomer) - single enantiomer >> racemic form. 37
- 38. β2 adrenergic receptor agonist • Salbutamol → Mixture of (R)-salbutamol and (S)- salbutamol • Levosalbutamol is the (R)-enantiomer → active bronchodilator. • Racemic & (S)-Salbutamol - Induce airway hyper responsiveness. - ↑ sensitivity to allergen. 38
- 39. Amlodipine • S-Amlodipine - active calcium channel blocker. R-Amlodipine - inactive calcium channel blocker. - mainly responsible for peripheral edema. • S-Amlodipine - effective at half the dose of racemate. - Incidence of peripheral oedema is negligible. 39
- 40. NSAIDs • Many are marketed as racemates. • Only naproxen is available as a single enantiomer. • Active form: S enantiomer (inactive R-enantiomer is partly inverted to active S form in vivo) • Dexibuprofen – ‘S’ enantiomer - Inhibition of COX activity Single enantiomer >> racemate 40
- 41. Some drugs are better as racemates • Both enantiomers of a chiral drug therapeutic effects, - single enantiomer may << racemic form. 41
- 42. β- blockers – • Most are marketed as racemates. • Both R & S propranolol ↓ formation of tri- iodothyronine from thyroxine. • R & S sotalol β-blocking & antiarrhythmic properties. • Timolol is marketed as the active S-enantiomer but both R & S-timolol reduce intraocular pressure. 42
- 43. Labetolol • Antihypertensive initially promoted as having both α and β-adrenergic antagonist properties • contains 2 asymmetric carbons - 4 optical isomers. • RR-labetalol: β-adrenoceptor antagonist properties SR-labetalol: α-adrenoceptor antagonist. others - essentially inactive. 43
- 44. RR- labetolol SR-labetolol • Dilevalol ( R,R-isomer ) – abnormal LFTs - withdrawn. 44
- 45. CONCLUSION • Stereoisomerism opened new avenues in the field of clinical pharmacology. •Each enantiomer - has its own pharmacologic profile • A single-enantiomer formulation of a drug may possess different properties than the racemic formulation. 45
- 46. • Increasing availability of single-enantiomer drugs - safer, better-tolerated, & more efficacious • Many existing racemates now replaced by single enantiomers. • Information from clinical trials & clinical experience should be used to decide which formulation is most appropriate. 46
- 47. REFERENCES 1. Pharmacology for pharmacy students – Dr. Padmaja Udaykumar 2. Chhabra N, Aseri ML, Padmanabhan D. A review of drug isomerism and its significance. Int J Appl Basic Med Res. 2013;3(1):16-8 3. McConathy J, Owens MJ. Stereochemistry in Drug Action. Prim Care Companion J Clin Psychiatry. 2003;5(2):70-73. 4. Salwe, Kartik & Gosavi, Devesh & Vimal, Deepti & k. Gupta, R. (2010). Pharmacological Significance of Stereoisomerism.. Journal of Mahatma Gandhi Institute of Medical Sciences. 15. 21-26. 5. Scott, A. K. (1990). Stereoisomers in Clinical Pharmacology. Drug Information Journal, 24(1), 121–123. 47
Editor's Notes
- Isomerism finds its importance in the field of clinical pharmacology and pharmacotherapeutics, as isomers differ in their pharmacokinetic and pharmacodyanmic properties. Currently, knowledge of isomerism has helped us in introducing safer and more effective drug alternatives of the newer as well as existing drugs.
- Isomers by definition are the molecules of identical atomic compositions, but with different bonding arrangements of atoms or orientations of their atoms in space i.e., isomers are two or more different substances with the same molecular formula.[3–5] Three types of isomerism are possible – Constitutional, Configurational, and Conformational. The terms configuration and conformation are often confused.
- Isomerism was first noticed in 1827, when Friedrich Woehler prepared silver cyanate and discovered that, although its elemental composition was identical to silver fulminate(prepared by Justus von Liebig the previous year),[14] its properties were quite different. This finding challenged the prevailing chemical understanding of the time, which held that chemical compounds could be different only when they had different elemental compositions. After additional discoveries of the same sort were made, such as Woehler's 1828 discovery that urea has the same atomic composition as the chemically distinct ammonium cyanate, Jöns Jacob Berzelius introduced the term isomerism in 1830 to describe the phenomenon. In 1848, Louis Pasteur separated tartaric acid into tiny crystals of its two mirror-image forms.[16][17] The individual molecules of each were the left and right optical stereoisomers, solutions of which rotate the plane of polarized light to the same degree but in opposite directions.
- Thalidomide was first marketed in 1957 in West Germany under the trade name Contergan. Primarily prescribed as a sedative or hypnotic, it was used against nausea and to alleviate morning sickness in pregnant women. Thalidomide became an over-the-counter drug in West Germany. Throughout the world, about 10,000 cases were reported of infants with phocomelia due to thalidomide; only 50% of the 10,000 survived. The part of the story that pertains to stereochemistry is that the original drug was made and sold as a mixture of 2 forms shown above. These are mirror images of each other, as you can see; they are not identical. Further research revealed that only the form on the right (the "R" form) was therapeutically active; the one on the leftthe "S" form) was not only ineffective, it was the source of the birth defects! Thalidomide is still used (rarely) for a variety of conditions. It is possible to make the compound in only one of the two forms, but because there is always some small proportion of the S-isomer, great pains are taken to avoid exposing women of childbearing age to it.
- Chirality and enantiomers Chirality is formally defined as the geometric property of a rigid object (like a molecule or drug) of not being superimposable with its mirror image. Chirality is often illustrated with the idea of left- and right-handedness: The best example of the chirality is our hand.; a left hand and right hand are mirror images of each other but are not superimposable. Any object can have this property, including molecules. A molecule is referred to as Chiral if it is not superimposable on its mirror image. Molecules that can be superimposed on their mirror images are achiral (not chiral). the term chiral was derived from the Greek word "cheir" meaning "hand"> and was applied as a description of the left- and right-handedness of crystal structure resulting from molecular asymmetry. The 2 mirror images of a chiral molecule are termed optical isomers because they rotate the plane of polarized light i.e, they are optically active. Today, optical isomers are more commonly referred to as enantiomers.
- A molecule is referred to as Chiral if it is not superimposable on its mirror image. Molecules that can be superimposed on their mirror images are achiral (not chiral). the term chiral was derived from the Greek word "cheir" meaning "hand"> and was applied as a description of the left- and right-handedness of crystal structure resulting from molecular asymmetry. The 2 mirror images of a chiral molecule are termed optical isomers because they rotate the plane of polarized light i.e, they are optically active. Today, optical isomers are more commonly referred to as enantiomers.
- Optical isomers or enantiomers have same physical and chemical properties like identical melting points, pKa, solubities, etc. But the important difference between two is that each member rotates the plane of polarized light to the same degree, in opposite directions. Most optical active drugs are chiral as a result of the presence of asymmetrically tetrahedral carbon atoms. Isomerization or enantiomerization is the conversion of one stereo-isomeric form into another (R-ibuprofen to S- ibuprofen). Both molecules of an enantiomer pair have the same chemical composition and can be drawn the same way in 2 dimensions (e.g., a drug structure on a package insert), but in chiral environments such as the receptors and enzymes in the body, they can behave differently.
- Nomenclature System The 2 enantiomers of a chiral drug are best identified on the basis of their absolute configuration or their optical rotation. I. Based on the optical activity 1. Dextrorotatory - Rotates plane of plane polarized light clockwise i.e. towards right direction and is denoted by d or + 2. Levorotatory - Rotates plane of plane polarized light clockwise i.e towards right direction and is denoted by l or – The limitation of this system is sign of rotation does not predict the absolute configuration of atom in enantiomer
- II. Based on configuration 1. D/L system This system considers the placement of group on the right and left. In this system projection should be in such a way that main carbon chain is positioned vertically The position of the principal substituent relative to carbon chain is identified. If it is to the right, then D configuration and if it is to the left then it is L configuration. D and L (note the upper case) are used for sugars and amino acids but are specific to these molecules and are not generally applicable to other compounds. Example D-Alanine L-Alanine Glyceraldehydes III. Based on R and S system8 Based on the tetrahedral structure of chemical entity. There are four groups bound to asymmetric carbon atoms, which are ranked. groups oriented by priority in clockwise fashion then it is termed as R isomer and if it is oriented in counter clockwise then S isomer. (is from the Latin rectus and means to the right or clockwise, and S is from the Latin sinister for to the left or counterclockwise.) Example: S-Glyceraldehyde R-Glyceraldehyde The terms d, or dextro, and l, or levo, are considered obsolete and should be avoided. Instead, the R/S system for absolute configuration and the +/− system for optical rotation should be used. Rule of 2n: Compounds with multiple centre of asymmetry such as Ephedrine have two chiral centres and Penicillin antibiotic have three chiral centres. In this case maximum number of stereoisomers possible can be calculated by Rule of 2n, where n = number of chiral centre in given molecule.2 So, for Ephedrine possible isomers are 22 = 4 (RR, SS, RS, SR) In penicillin there are three chiral carbon atoms so possible isomers are 23 = 8 But the only naturally biosynthesized examples are 3S, 5R, 6R enantiomer displays significantly antibacterial activity.
- When two similar or higher priority groups are attached to the carbon on the same side, it is termed as Cis isomer and when it is attached to the opposite side it is called as Trans isomer.
- III. Based on R and S system8 Based on the tetrahedral structure of chemical entity. There are four groups bound to asymmetric carbon atoms, which are ranked. groups oriented by priority in clockwise fashion then it is termed as R isomer and if it is oriented in counter clockwise then S isomer. (is from the Latin rectus and means to the right or clockwise, and S is from the Latin sinister for to the left or counterclockwise.) Example: S-Glyceraldehyde R-Glyceraldehyde The terms d, or dextro, and l, or levo, are considered obsolete and should be avoided. Instead, the R/S system for absolute configuration and the +/− system for optical rotation should be used. Rule of 2n: Compounds with multiple centre of asymmetry such as Ephedrine have two chiral centres and Penicillin antibiotic have three chiral centres. In this case maximum number of stereoisomers possible can be calculated by Rule of 2n, where n = number of chiral centre in given molecule.2 So, for Ephedrine possible isomers are 22 = 4 (RR, SS, RS, SR) In penicillin there are three chiral carbon atoms so possible isomers are 23 = 8 But the only naturally biosynthesized examples are 3S, 5R, 6R enantiomer displays significantly antibacterial activity.
- CHIRAL DRUGS IN BIOLOGICAL SYSTEMS Enantiomers of a chiral drug have identical physical and chemical properties in an achiral environment. In a chiral environment, one enantiomer may display different chemical and pharmacologic behavior than the other enantiomer. Because living systems are themselves chiral, each of the enantiomers of a chiral drug can behave very differently in vivo. In other words, the R-enantiomer of a drug will not necessarily behave the same way as the S-enantiomer of the same drug when taken by a patient. For a given chiral drug, it is appropriate to consider the 2 enantiomers as 2 separate drugs with different properties unless proven otherwise. The difference between 2 enantiomers of a drug is illustrated in Figure 1 using a hypothetical interaction between a chiral drug and its chiral binding site. In this case, one enantiomer is biologically active while the other enantiomer is not. The portions of the drug labeled A, B, and C must interact with the corresponding regions of the binding site labeled a, b, and c for the drug to have its pharmacologic effect. The active enantiomer of the drug has a 3-dimensional structure that can be aligned with the binding site to allow A to interact with a, B to interact with b, and C to interact with c. In contrast, the inactive enantiomer cannot bind in the same way no matter how it is rotated in space. Although the inactive enantiomer possesses all of the same groups A, B, C, and D as the active enantiomer, they cannot all be simultaneously aligned with the corresponding regions of the binding site. This difference in 3-dimensional structure prevents the inactive enantiomer from having a biological effect at this binding site. In these instances, the individual enantiomers may display very similar or even equivalent pharmacology at their target site. Even in these cases, the enantiomers may differ in their metabolic profiles as well as their affinities for other receptors, transporters, or enzymes.
- The difference between 2 enantiomers of a drug is illustrated in Figure 1 using a hypothetical interaction between a chiral drug and its chiral binding site. In this case, one enantiomer is biologically active while the other enantiomer is not. The portions of the drug labeled A, B, and C must interact with the corresponding regions of the binding site labeled a, b, and c for the drug to have its pharmacologic effect. The active enantiomer of the drug has a 3-dimensional structure that can be aligned with the binding site to allow A to interact with a, B to interact with b, and C to interact with c. In contrast, the inactive enantiomer cannot bind in the same way no matter how it is rotated in space. Although the inactive enantiomer possesses all of the same groups A, B, C, and D as the active enantiomer, they cannot all be simultaneously aligned with the corresponding regions of the binding site. This difference in 3-dimensional structure prevents the inactive enantiomer from having a biological effect at this binding site. In these instances, the individual enantiomers may display very similar or even equivalent pharmacology at their target site. Even in these cases, the enantiomers may differ in their metabolic profiles as well as their affinities for other receptors, transporters, or enzymes.
- IMPORTANCE OF CHIRALITY IN DRUGS Approximately 50% of marketed drugs are chiral, and of these approximately 50% are mixtures of enantiomers rather than single enantiomers. The 2 enantiomers of a chiral drug may differ significantly in their bioavailability, rate of metabolism, metabolites, excretion, potency and selectivity for receptors, transporters and/or enzymes, and toxicity (pharmacokinetic and pharmacodynamic differences).
- Pharmacokinetic differences resulting out of stereoisomerism are as follows: Absorption: L methotrexate is better absorbed than its isomer D Methotrexate similarly Esmoprazole is more bioavailable than racemic Omeprazole.
- 2. Distribution: S warfarin is more extensively bound to albumin than R Warfarin. Hence it has lower volume of distribution. Similarly the volume of distribution of Levocetrizine is smaller than that of its dextro enantiomer, which is a positive aspect in terms of both safety and efficacy. Similaraly d propanolol is more extensively bound than l propanolol
- 3. Metabolism Warfarin isomers are metabolized by different routes. The S form is more potent and is metabolized relatively faster by ring oxidation, while R form is less potent and degraded by side chain reduction.11 R warfarin is oxidized to 6 hydroxywarfarin and then it is reduced to (R, S) warfarin alcohol.S warfarin is oxidized to 7 hydroxywarfarin and then it is reduced to (S, S) warfarin alcohol Half life of S-warfarin is 32 hours,wh ere as that of R-warfarin is 54 hours. Pharmacodynamics differences resulting out of stereoisomerism are as follows: Potency: l Propanolol has powerful β blocking actions (eutomers) while d propanolol is inactive (diastomer) 2. S warfarin is more potent anticoagulant than R warfarin. 3. The S form of the ibuprofen is active but R form is inactive.
- 2) Pharmacological action: Quinine has antimalarial property while quinidine is an antiarrhythmic drug. 2. l sotalol has β blocking action while d sotalol has antiarrhythmic action. 3. L methorphan is a potent opioid analgesic while Dextromethorphan is a cough suppressant. 4.
- S ketamine is potent anasthetics while R ketamine is hallucinogenic in nature. 5. (+) 2R, 3S propoxyphene is analgesic while (-) 2S, 3R propoxyphene is an antitussive agent. 6. Nebivolol has highly selectively beta-1-blocking effects, while the L-isomers causes vasodilatation; 7. Salbutamol is available as a single isomeric preparation of R-isomer as levalbuterol
- 3) Therapeutic and adverse effects R thalidomide is sedative while S thalidomide exhibits teratogenic effect. However, the individual enantiomers of thalidomide are both inverted rapidly to the recemic mixture in the liver. Hence the claims that the thalidomide tragedy could have been prevented using single R-enantiomer of thalidomide is not valid. 2. R-Naproxane is used to treat arthralgic pain while S-Naproxane is teratogenic 3. D ethambutol is used to treat TB while L ethambutol causes blindness.
- 4. (S) (+)-ketamine causes fewer psychotic emergence reactions, less agitated behavior, and better intraoperative amnesia, and analgesia than its enantiomer; 5. L-dopa, used in treatment for Parkinson's disease has an isomer D-dopa which has never been used because it causes deficiency of white blood cells and thus susceptibility to infections
- 4) Efficacy S (-) carvediol is 100 times more potent as β blocker than R (-) carvedilol however their α receptor blocking action is equipotent. 2. S timolol is more potent β receptor antagonist than R timolol but both reduce intra ocular tension to same extent.
- 5) Drug interaction : Two stereoisomers can compete for binding to the same receptor S methadone antagonizes respiratory depressant action of R methadone. 2. If the two isomers are of agonist and antagonist type then recemic mixture acts as partial agonist for example Picendol, an Opioid analgesic drug (+) (3S, 4R) enantiomer is pure agonist (-) (3R, 4S) enantiomer is pure antagonist (+) (3RS, 4RS) racemic mixture partial agonist
- Metronidazole and sulfinpyrazone inhibit the metabolism of S warfarin strongly as opposed to R warfarin. 4. Metabolic interconversion is common with aryl alkalonic acid like Ibuprofen R--------------------------S Single active enantiomer: To overcome these pharmacological differences, using a single enantiomer is many times preferred over racemic mixtures. Many drugs which were marketed previously as racemic mixtures are now available as single enantiomers.
- Single Enantiomers vs. Racemic Mixtures A mixture of equal portion 50:50 of the + and – enantiomers is called racemic mixture and are optically inactive. approximately 50% of chiral drugs are marketed as mixtures of enantiomers rather than single enantiomers. both the single-enantiomer form and the mixture of enantiomers of a given drug may be available at the same time. In these cases, it is critical to distinguish the single enantiomer from the racemic form because they may differ in their dosages, efficacies, side effect profiles, or even indicated use. The decision to use a single enantiomer versus a mixture of enantiomers of a particular drug should be made on the basis of the data from clinical trials and clinical experience.
- Single enantiomers have less complex and more selective pharmacodyanamic profile as compared to racemic mixture, so have lesser adverse drug reactions, improved therapeutic profile, less chances of drug interactions than racemic mixtures. patients are also exposed to less amount of drug so body is exposed to the lesser metabolic, renal and hepatic load of drug, there is easier therapeutic drug monitoring of the active pure active enantiomers Other drugs marketed now as single enantiomers - Escitalopram, Naproxen, etc.
- Examples of racemic mixtures and the corresponding single enantiomer products that have been marketed include: 1. Amphetamine and Dextroamphetamine 2. Bupivacane and levobupivacane 18 3. Ofloxacin and Levofloxacin19 4. albuterol and Levalbuterol 20 5. Omeprazole and Esmoprazole21 6. Cetrizine and Levocetrizine
- Currently, there is no regulatory mandate in the United States or Europe to develop new drugs exclusively as single enantiomers. Although both racemic and single-enantiomer drugs will continue to be developed, a higher proportion of single enantiomers are being submitted for new drug approval. Although many psychotropic drugs are either achiral (e.g., fluvoxamine, nefazodone) or are already marketed as single enantiomers (e.g., sertraline, paroxetine, escitalopram), a number of antidepressants are currently marketed as racemates. Selected racemic drugs used in psychiatric practice are listed in Table 1.
- Other drugs – β2 ADreNErgic recePTOR AGONIST Salbutamol • Salbutamol →Mixture of (R)-salbutamol and (S)-salbutamol • Levosalbutamol is the (R)-enantiomer → active bronchodilator. Racemic and (S)-Salbutamol • Induce airway hyper responsiveness. • Increase sensitivity to allergen challenge. • Inhalation of levosalbutamol→ greater bronchodilatation than the equivalent dose of the racemate.
- S-AMLODIPINE • S-Amlodipine → active calcium channel blocker. • R-Amlodipine → inactive as calcium channel blocker. • Mainly responsible for peripheral edema. • Treatment of hypertension. • S-Amlodipine is effective at half the dose of racemate. • Incidence of peripheral oedema is negligible. • Treatment of normotensive angina patients. • S-Amlodipine is effective at half the dose of racemate.
- NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) Like the /3-blockers many of the NSAIDs are marketed as racemates. Only naproxen is available as a single isomer. The S-enantiomer is the active form but in vivo the inactive R-enantiomer is partly inverted to the active S form. Most adverse effects are related to the mechanism of action of the NSAIDs and would not be helped by administration as a single enantiomer. Dexibuprofen • Inhibition of cyclooxygenase activity – „S’ enantiomer. • 60% of R enantiomer undergoes chiral inversion to the active S-enantiomer. • chiral Dexibuprofen (1200 mg daily) was better than racemate (2400 mg daily). • Highly effective NSAID. • Low adverse effect profile
- Some drugs are better as racemates β- ADRENOCEPTOR ANTAGONISTS Most of the /3-blockers are marketed as racemates. The S-enantiomer is responsible for the /3-adrenoceptor antagonist activity but the d-enantiomer may have other properties. Both R and S propranolol reduce the formation of tri-iodothyronine from thyroxine. The R-enantiomer of sotalol prolongs the QT C interval and has antiarrhythmic properties. Cimetidine stereoselectively inhibits the first pass metabolism of R-metoprolol but since this enantiomer is inactive at the /3-receptor there was no pharmacodynamic effect. Timolol is marketed as the active Senantiomer but both R and S-timolol reduce intraocular pressure.
- LABETALOL Labetalol is an antihypertensive agent that was initially promoted as having both α and /3-adrenergic antagonist properties in a single molecule. However, labetalol contains two asymmetric carbons and therefore has four optical isomers. RR-labetalol is responsible for the ^-adrenoceptor antagonist properties while SR-labetalol is an α-adrenoceptor antagonist. The other isomers are essentially inactive. • Dilevalol ( R,R-isomer ) – elevated liver function tests. • Chiral dilevalol was withdrawn.
- To conclude, the field of stereoisomerism is all fascinating and challenging. Research in the field of stereoisomerism has opened the new challenges and the new field avenues in the field of clinical pharmacology. The increasing availability of single-enantiomer drugs promises to provide clinicians with safer, better-tolerated, and more efficacious medications for treating patients. Many existing recemates are now replaced by single enantiomers with improved efficacy and tolerability.