This document provides an overview of stereoisomers in pharmacology. It begins with an introduction to stereochemistry and the clinical importance of isomerism. It then discusses the basic concepts of isomerism including constitutional, configurational, and conformational isomers. It focuses on chirality and defines enantiomers, noting that while they have identical physical and chemical properties, they can behave differently in biological systems. The document reviews the history of isomerism discoveries and provides examples of how stereoisomers can have different pharmacological and pharmacokinetic properties. It discusses the importance of considering single enantiomers versus racemic mixtures in drug development and concludes that a single enantiomer formulation may have advantages over the racemic form

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
= 𝟐𝒏 ( Rule of 2𝑛 )
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 V
d
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.
• 𝐭𝟏/𝟐 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)
Stimolol 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
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