…….. “DRUGS” do something in our body as a result of their molecular structure, which determines: 1. Physicochemical properties 2. Chemical / biochemical reactivity 3. Shape 4. STEREO-CHEMISTRY

1. STEREOISOMERS
Dr.ARAVINDA KUMAR.B
Dept. of Pharmacology,
PIMS.

2. OUTLINE
 INTRODUCTION
 HISTORY OF CHIRALTY
 TYPES & NOMENCLATURE OF ISOMERS
 CHIRAL DRUGS – INTRODUCTION
 FDA REGULATIONS IN DEVELOPING CHIRAL DRUGS
 ROLE OF STEREOISOMERS IN PHARMACOLOGY –
KINETICS, DYNAMICS, ADVERSE EFFECTS
 PHARMACEUTICAL INDUSTRY & CHIRAL DRUGS
 SUMMARY

3. …….. “DRUGS” do something in our body as a result of
their molecular structure, which determines:
 Physicochemical properties
 Chemical / biochemical reactivity
 Shape
 STEREOCHEMISTRY

4. STEREOISOMERS
• Stereoisomers are molecules with one or more
“chiral” centres that allow the possibility of forms
with the same chemical formula but differing
spatial arrangements.

5. STEREOISOMERS
GEOMETRIC
ISOMERS
OPTICAL
ISOMERS
ENANTIOMERS DIASTEREOISOMERS

6. HISTORY

7. CHEIR means “hand” in Greek

9. Terminologies
 A compound containing an equal proportion of
each enantiomer is called a racemic mixture.
 Chiral switching - development of single
enantiomers from old racemate drugs
 Chiral inversion is the conversion of one
stereoisomeric form into another (ie, R-ibuprofen
to S-ibuprofen)

10. NOMENCLATURE – 3ways
 According to rotation of polarized light
(+) and (-); dextro or levo rotatory
 D/L – w.r.t glyceraldehyde
 R/S enantiomers - Cahn-Ingold-Prelog priority
rules

12. CHIRAL DRUGS -Easson-Stedman
Model (1993)

13. Greatest differences between a pair of enantiomers occur at
the level of receptor interactions.
 Eutomer: enantiomer with higher affinity/activity.
 Distomer: enantiomer with lower affinity/activity.
 Eudismic Ratio: Ratio of the Eutomer/Distomer affinities
or activities.

16. Racemic drugs with one major
bioactive enantiomers
 Cardiovascular drugs – BBs, CCBs, ACE
inhibitors
 Neurology/Psychiatric drugs – barbiturates,
opiates, anticonvulsants, psychostimulants
 Others – anti-arrhythmics, antibiotics,
hypolipidemics, PPIs, anticoagulants,
antihistamines

18. Racemic drugs with equally
bioactive enantiomers
 cyclophosphamide (antineoplastic)
 flecainide (antiarrhythmic)
 fluoxetine (antidepressant)

19. Racemic drugs with chiral
inversion
 Unidirectional - NSAIDS (S-isomer 100 times
more potent )
 Bidirectional - 3-hydroxy-benzodiazepines
(oxazepam, lorazepam, temazepam) and
thalidomide

20. Advantages of Chiral
switching
 Separating unwanted PD side effects from toxic
effects if these reside exclusively in one
enantiomer
 Expose the patient to less body load and thus
reduce metabolic/hepatic/renal dug load
 Easier assesment of physiology, disease and drug
co-administration effects

21. Advantages of Chiral
switching…
 Reduce DI / avoid enantiomer-enantiomer
interaction/ avoid bioinversion
 Easier assessment of efficacy & toxicity through
PD/PK monitoring of pure enantiomers

22. PHARMACOKINETIC &
PHARMACODYNAMIC IMPLICATIONS
OF CHIRALTY
 Bioavailability (esomeprazole)
 Volume of distribution (Levocetrizine)
 Drug metabolizing enzyme systems – differ in
rates of metabolism
 Cytochrome enzyme induction or inhibition

23. CHIRAL - formulations &
excipients
 Improve solubility, dissolution and stability
 Celluloses / Starch, sugars & derivatives /
Cyclodextrins / Acids / Amino acids, peptides &
derivatives / Fats, oils and essential oils

25. CHIRALTY – Role in Kinetics &
Dynamics
 Selective beta-1 activity is enhanced (even in
higher doses)
 CYP2D6 polymorphism
S-atenolol S-metoprolol

26. CHIRALTY – Role in Kinetics &
Dynamics
 Independent of CYP2C19
 Metabolized by CYP3A4/sulfotransferases

27. CHIRALTY – Role in Kinetics &
Dynamics
 Small Vd
 Low hemato-encephalic barrier passage; low cerebral receptor binding
 Enhanced specific periphery H1 receptor binding

28.  2-3 times more potent than racemic
 Rapidly eliminated (R-isomer inhibits S-isomer’s elimination)
 Smoother emergence period, profound post-op analgesia, more rapid recovery of cerebral
function
 Psychotomimetic phenomenon – negligibly less.
CHIRALTY – Role in Kinetics &
Dynamics

31. ROLE OF CHIRAL DRUGS IN
PREVENTING ADRs
(CH3)2CHCH2
COOH
H
CH3 CH2CH(CH3)2
HOOC
H
H3C
(-)-(R)-ibuprofen (+)-(S)-ibuprofen

32. ROLE OF CHIRAL DRUGS IN
PREVENTING ADRs
 Most widely used long acting local anesthetic
 Fatal cardiotoxicity – racemate.

33. ROLE OF CHIRAL DRUGS IN
PREVENTING ADRs
Chiral
inversion

34. ROLE OF CHIRAL DRUGS IN
PREVENTING ADRs
- Vasodilation
- Increased t1/2
- Decreased peripheral edema
- Safer & long acting

35. ROLE OF CHIRAL DRUGS IN
PREVENTING ADRs

36. ROLE OF CHIRAL DRUGS IN
PREVENTING ADRs
• Levorotatory R-salbutamol & dextrorotatory S-salbutamol
• S-salbutamol -- increases airway hyper-reactivity

37. ROLE OF CHIRAL DRUGS IN
PREVENTING ADRs
• R-Albuterol (levalbuterol)– bronchodilator activity
• S-Albuterol - antagonizes the effect of R-albuterol, pro-inflammatory effects.

38. ROLE OF CHIRAL DRUGS IN
PREVENTING ADRs
Wilson’s disease blindness & toxic

39. FAILURES OF CHIRAL
SWITCHING
 Fenfluramine/dexfenfluramine
 Sotalol
 Dilevalol
 Fluoxetine

40. DILEVALOL – R,R isomer of labetalol
(hepatotoxic)

41. Chiral Switch : Problems
 Sotalol (-) VS (+)
 (-)- enantiomer 14 to 50 fold more potent
as a β-blocker; equipotent as
antiarrhythmic.
 SWORD trial

42. Chiral Switch : Problems

43. Chiral Switch : Problems
 Dexfenfluramine / Fenfluramine:
anoretic agent; racemic drug had been
available for 25 years.
 Valvular heart disease & Pulmonary
hypertension (FEN-PHEN)
 Both single enantiomer and racemate
voluntarily withdrawn.

44. PHARMACEUTICAL INDUSTRY &
CHIRAL SWITCHES
 Launching chirally pure drugs from racemates –
time & monetory investments on its chemical
separation and clinical evaluation
 Ensure its return on investments
 Innovation in health care system and merits
incentives in the form of patents.

46. REFERENCES
 Patil PA, Kothekar MA. Development of safer
molecules through chirality. Indian J Med
Sci.2006 Oct;60(10):427-37
 Lien AN, Hua H, Chuong PH. Chiral Drugs: An
Overview. Int J Biomed Sci. 2006 June; 2(2): 85-
100
 Tucker GT. Chiral switches. Lancet
2000;355:1085-7
 Burke D, Henderson DJ. Chiralty: a blue print for
the future. J Anaesth 2002;88:563-76