stereochemistry&nomenclature,case studies

2. STEREOCHEMISTRY AND DRUG ACTION
PRESENTED BY:
MOUNIKA.PERLI
I/II M.PHARMACY
REG NO:Y18MPH0225
UNDER THE GUIDENCE OF
RAMALINGESWARARAO.KASULA
(M.PHARM)
HINDU COLLEGE OF PHARMACY

3. CONTENTS
• STEREOCHEMISTRY
• TYPES OF ISOMERS
• CHIRALITY OF DRUGS
• EXAMPLES OF CHIRAL DRUGS
• PHARMACOKINETICS STEREOSELECTIVITY

4. stereochemistry
A branch of chemistry
that deals with the
spatial arrangement of
atoms and groups in
molecules
"stereo”- means “three
dimensionality’’

5. IMPORTANT DEFINITIONS
• CHIRALITY:
A chiral molecule/ion is non-
superposable on its mirror
image. The presence of an
asymmetric carbon center
is one of several structural
features that induce chirality in
organic and inorganic molecules.

6. • STEREOISOMERS: Isomers that have same molecular
formula and connectivity but differ in a way that
atoms are oriented in space – i.e; Difference between
isomers lies only in 3D arrangements of atoms.

7. • ENANTIOMER: Greek word: enantio : opposite
merons : parts
Stereoisomers with non superimposable mirror
images.
• DIASTEREOMER : Diastereomers are
stereoisomers that are not mirror images of
one another and are non-superimposable on
one another. Stereoisomers with two or more
stereocenters can be diastereomers.

8. TYPES OF ISOMERISMS

9. Stereoisomers
1. Configurational isomer :
# Geometric isomers :
(a) cis & trans system / E & Z system
# Relative configuration / Fischer projection ( L & D
configuration)
# Absolute configuration (R & S configuration)

10. L & D CONFIGURATION

11. R & S CONFIGURATION
•Priority of an atom is determined
by its atomic number
• Order of substituents going
from highest to lowest priority.
• Clockwise – R (rectus).
• Anticlockwise – S (sinister).
• Unless established
experimentally no idea whether
(+) or (-) rotation is associated
with R or S configuration

12. CHIRALITY OF DRUGS
• Chiral center arises when a carbon atom has
four structurally different groups attach to it.
• When a compound contain one or more
chiral center it is able to rotate plane polarized
light to the right (+) or the left (-)
• E.g; Adrenaline can exist as two Enantiomers
that are mirror images of each others and thus
known as non-superimposable

13. ADRENALINE
• Adrenaline Enantiomers have identical ,physical and
chemical properties , the only in their properties is that the
Enantiomers rotate plane polarize light in opposite
direction , both Enantiomers have different biological
properties
• The negative Enantiomers exert stronger effect i.e; Heart
rate increases
• Device which is used to determine the direction in which a
molecule rotate plane polarize light is polarimeter.
• X-ray crystallography of adrenaline Enantiomers shown
that negative form has R configuration and the positive
form has S configuration

14. Importance of the chirality in drugs
• This stereoisomerism results in different physical and
chemical properties of the compound. If this compound
happens to be drug then it results in different
pharmacokinetic and pharmacodynamic properties
• The importance of chiral drugs in the drug development
space cannot be understated. In pharmaceutical industries,
56% of the drugs currently in use are chiral molecules and
88% of the last ones are marketed as racemates (or racemic
mixtures), consisting of an equimolar mixture of two
enantiomers.

15. Thalidomide-disastrous biological
activity of the wrong enantiomer
• In 1960 in Europe, racemic thalidomide
was given to pregnant females to cure
morning sickness.
• This led to deformations in babies and
neurotoxic effects.
• These were due to S-thalidomide.
• R-thalidomide contained the desired
therapeutic activity

16. EXAMPLES OF CHIRAL DRUGS
• INTRAVENOUS ANAESTHETICS
• LOCAL ANAESTHETICS
• INHALATIONAL AGENTS
• NUEROMUSCULAR BLOCKING AGENTS
• SOME OTHER DRUGS

17. Intravenous anaesthetics
1.Etomidate
• Administered as a single isomer: R-isomer.
• Site of action: GABAA receptor.
• R-isomer is 15 times more potent than the S-isomer.
• S-isomer lacks hypnotic activity.

18. 2. Ketamine
• S- Ketamine is 2-4 times more potent than R Ketamine as an
anaesthetic and analgesic agent.Rketamine: Emergence
reactions like hallucinations, vivid dreams and agitation
•Metabolism of S- Ketamine by liver microsomes is 20%
greater than R- Ketamine and 10% greater than the racemate
– faster clearance of the drug.

19. LOCAL ANAESTEHTICS
1.BUPIVACAINE
Long acting local anaesthetic marketed as 50:50 racemic
mixture.
Reports of death due to
• Bupivacaine induced CNS toxicity and
cardiotoxicity on accidental intravenous injection
and difficult resuscitation following cardiotoxicity.
Safer alternatives
• Levobupivacaine
• Ropivacaine
These are S- enantiomers of bupivacaine.
• Ropivacaine is the first ‘pure’ enantiomer containing
>99% of the S-form.

20. INHALATIONAL AGENTS
Isoflurane
•Some studies have found S(+)-isoflurane to be 50%
more potent than R(-)- isoflurane while other studies
have found no significant difference.
•Both enantiomers are equally soluble in the lipid bilayers.
•S- isoflurane induced about 50% longer sleep
times than R- isoflurane
•Majority of the inhalational agents
•currently used are chiral except, Sevoflurane

21. NEUROMUSCULAR BLOCKING AGENTS
1. Atracurium
• Intermediate duration non-depolarizing
neuromuscular blocker.
• Causes histamine release, transient hypotension,
tachycardia, facial or truncal flushing.
• Continuous infusion in critical patients can lead to
laudanosine accumulation, which is
epileptogenic.
• Its structure contains 4 chiral centres and is a
mixture of 10 optical and geometric isomers.

22. Potential advantages of single
enantiomer products
• Less complex, more selective
pharmacodynamic profile
• Potential for an improved therapeutic index
• Less complex pharmacokinetic profile
Reduced potential for complex drug interactions
• Less complex relationship between
plasma concentration and effect

23. Biological Discrimination

24. Pharmacokineticsstereoselectivity
1.Absorption
* Passive intestinal absorption
* Carrier transporter stereoselectivity
2.Distribution
* Protein binding
* Tissue distribution
3.Metabolism
* first pass metabolism
* Phase I and phase II metabolism
4.Elimination

25. Absorption and stereoselectivity
Passive intestinal absorption
For the majority of racemic drugs, absorption appears
to be by passive diffusion , provided no
stereoselectivity.

26. Carrier mediated
transporter
Stereo selective
intestinal transporter is
the main cause for
marked differences in
the oral absorption of
enantiomers.
L-Methotrexate have
40 fold higher Cmax
and AUC than
D-Methotrexate.

27. Distribution
Protein binding
Stereo selective plasma protein binding could influence
distribution and elimination because the major
determinant of drug distribution and elimination is
protein binding.
The enantiomers may display different magnitudes of
stereoselectivity between the various proteins found in
plasma

28. Ex// the R- propranolol binding to albumin is greater than
S- propranolol and the opposite is observed for 1 -acid
glycoprotein.
* Highly albumin bound
* Less potent
*highly bound to AAG
available as unbound
* 40-100 time more
potent

29. Metabolism
first pass metabolism
Stereo selective drug
metabolism is commonly
observed in vitro for
racemic drugs and can
results in substantial
differences in the vivo
plasma concentration -
time profiles between
enantiomers due to
stereo selective
bioavailability or drug
disposition.

30. Phase I and phase II metabolism
The magnitude of stereoselectivity depends on the
metabolic pathways involved drug metabolism.

31. some time the two isomers compete with each
other to bind the enzyme binding site, this result in
inhibition the metabolism of the one enantiomer.
Ex// propaphenon

33. REFERENCES
• https://www.slideshare.net/AZMINMOGAL/stereoch
emistry-83184901?qid=6fc35486-740a-
45b083bdf812d3804882&v=&b=&from_search=3
• https://www.slideshare.net/arzoodharasandiya/case
-study-of-stereochemistry-and-drug-design-
85443779?qid=6fc35486-740a-45b0-83bd-
f812d3804882&v=&b=&from_search=2
• https://www.slideshare.net/rudramadhab1/chiral-
drug?qid=37d78d5f-a23d-4f72-8268-
08b3b65105f7&v=&b=&from_search=7