Stereoisomers in pharmacology

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 1 st 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 morning 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 = ( Rule of ) n = number of chiral centres Eg. Ephedrine – 2 chiral centres = 4 isomers (RR, RS, SS & SR)   12

13. Nomenclature System Based on the optical activity – Dextrorotatory - Rotates plane polarized light towards right (clock-wise) ‘ d ’ or ‘ + ’ Levorotatory - Rotates plane polarized light towards left (anti-clockwise) ‘ l ’ or ‘ – ’ Limitation: sign of rotation does not predict absolute configuration of atom 13

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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. Cis-/ Trans-isomer 2 similar / higher priority groups attached to 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

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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 Absorption: L methotrexate is better absorbed than D Methotrexate Esomeprazole is more bioavailable than racemic Omeprazole. 23

24. 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. 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. of S-warfarin - 32 hours, R-warfarin - 54 hours.   25

26. Examples of PD differences 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 Pharmacology for pharmacy students – Dr. Padmaja Udaykumar 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 McConathy J, Owens MJ. Stereochemistry in Drug Action.  Prim Care Companion J Clin Psychiatry . 2003;5(2):70-73. 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. Scott, A. K. (1990). Stereoisomers in Clinical Pharmacology.  Drug Information Journal ,  24 (1), 121–123.  47