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
stereochemistry and drug action ; basic introduction about stereochemistry and stereoisomers ; pharmacokinetic and pharmacodynamics concept of stereochemistry ; easson Stedman hypothesis ; stereo selectivity criteria .
stereochemistry and drug action ; basic introduction about stereochemistry and stereoisomers ; pharmacokinetic and pharmacodynamics concept of stereochemistry ; easson Stedman hypothesis ; stereo selectivity criteria .
e-content of Stereochemistry for Pharmacy and Chemistry students.
contents includes Isomerism, Chirality, Stereoisomers, Enantiomer, Diastereomer, Cis And Trans Configuration ,L And D Configuration ,R And S Configuration and Importance of the chirality in drugs ,Intravenous anaesthetics , etc.
this presentation describes ways to enantiomeric product synthesis, hence introducing to chiral catalysts. the temperature effects are discussed with relation to soai autocatalysis. it shows introduction to stereocartography.
…….. “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
Stereochemistry is the ‘chemistry of space’ , that is stereochemistry deals with the spatial arrangements of atoms and groups in a molecule.
Stereochemistry can trace its roots to the year 1842 when the French chemist Louis Pasteur made an observation that the salts of tartaric acid collected from a wine production vessel have the ability to rotate plane-polarized light, whereas the same salts from different sources did not have this ability.
Isomers are compounds that contain exactly the same number of atoms, i.e., they have exactly the same empirical formula, but differ from each other by the way in which the atoms are arranged.
Constitutional isomers, also known as structural isomers, are specific types of isomers that share the same molecular formula but have different bonding atomic organization and bonding patterns.
Stereoisomers are molecules having the same molecular formula and the atomic arrangement, but differ in their spatial arrangement.
Geometric isomers are two or more coordination compounds which contain the same number and types of atoms, and bonds (i.e., the connectivity between atoms is the same), but which have different spatial arrangements of the atoms.
There are 2 types of geometric isomers, ‘cis’ and ‘trans’.-cis isomers: when similar groups are present on the same side of the double bonds, then they are termed as cis.- trans isomers: when similar groups are present on the opposite sides of the double bonds then they are called trans isomers.
cis-diethylstilbestrol has only 7% of the estrogenic activity of trans-diethylstilbesterol.
Cisplatin have anticancer activity where ae trans platin is an inactive compound.
In chemistry, a molecule or ion is called chiral if it cannot be superposed on its mirror image by any combination of rotations, translations, and some conformational changes.
Chirality is the property of being non identical to ones mirror image.
Chiral center is defined as the atom bearing 4 different atoms or group of atoms.
Molecules that form nonsuperimposable mirror images, and thus exist as enantiomers, are said to be chiral molecules.
For a molecule to be chiral, it cannot contain a plane of symmetry.
The term enantioselectivity refers to the efficiency with which the reaction produces one enantiomer.
Enantiomers are stereoisomers that are non-superimposable mirror images.
Have identical properties.
Similar shapes
Diastereomers are stereoisomers that are non superimposable and are not mirror images.
Have distinct physical properties.
Have different molecular shapes.
Enantiomers consist of a pair of molecules that are mirror images of each other and are not superimposable.
When a molecule contains only one chiral centre , the two stereoisomers are known as enantiomers.
These may be referred to or labelled using the configurational descriptors as either:
R(rectus meaning right handed) or S(sinister meaning left handed),
D(dextrorotatory)or L (laevorotatory)
E-Entgegen or Z- Zusamen
e-content of Stereochemistry for Pharmacy and Chemistry students.
contents includes Isomerism, Chirality, Stereoisomers, Enantiomer, Diastereomer, Cis And Trans Configuration ,L And D Configuration ,R And S Configuration and Importance of the chirality in drugs ,Intravenous anaesthetics , etc.
this presentation describes ways to enantiomeric product synthesis, hence introducing to chiral catalysts. the temperature effects are discussed with relation to soai autocatalysis. it shows introduction to stereocartography.
…….. “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
Stereochemistry is the ‘chemistry of space’ , that is stereochemistry deals with the spatial arrangements of atoms and groups in a molecule.
Stereochemistry can trace its roots to the year 1842 when the French chemist Louis Pasteur made an observation that the salts of tartaric acid collected from a wine production vessel have the ability to rotate plane-polarized light, whereas the same salts from different sources did not have this ability.
Isomers are compounds that contain exactly the same number of atoms, i.e., they have exactly the same empirical formula, but differ from each other by the way in which the atoms are arranged.
Constitutional isomers, also known as structural isomers, are specific types of isomers that share the same molecular formula but have different bonding atomic organization and bonding patterns.
Stereoisomers are molecules having the same molecular formula and the atomic arrangement, but differ in their spatial arrangement.
Geometric isomers are two or more coordination compounds which contain the same number and types of atoms, and bonds (i.e., the connectivity between atoms is the same), but which have different spatial arrangements of the atoms.
There are 2 types of geometric isomers, ‘cis’ and ‘trans’.-cis isomers: when similar groups are present on the same side of the double bonds, then they are termed as cis.- trans isomers: when similar groups are present on the opposite sides of the double bonds then they are called trans isomers.
cis-diethylstilbestrol has only 7% of the estrogenic activity of trans-diethylstilbesterol.
Cisplatin have anticancer activity where ae trans platin is an inactive compound.
In chemistry, a molecule or ion is called chiral if it cannot be superposed on its mirror image by any combination of rotations, translations, and some conformational changes.
Chirality is the property of being non identical to ones mirror image.
Chiral center is defined as the atom bearing 4 different atoms or group of atoms.
Molecules that form nonsuperimposable mirror images, and thus exist as enantiomers, are said to be chiral molecules.
For a molecule to be chiral, it cannot contain a plane of symmetry.
The term enantioselectivity refers to the efficiency with which the reaction produces one enantiomer.
Enantiomers are stereoisomers that are non-superimposable mirror images.
Have identical properties.
Similar shapes
Diastereomers are stereoisomers that are non superimposable and are not mirror images.
Have distinct physical properties.
Have different molecular shapes.
Enantiomers consist of a pair of molecules that are mirror images of each other and are not superimposable.
When a molecule contains only one chiral centre , the two stereoisomers are known as enantiomers.
These may be referred to or labelled using the configurational descriptors as either:
R(rectus meaning right handed) or S(sinister meaning left handed),
D(dextrorotatory)or L (laevorotatory)
E-Entgegen or Z- Zusamen
Operation “Blue Star” is the only event in the history of Independent India where the state went into war with its own people. Even after about 40 years it is not clear if it was culmination of states anger over people of the region, a political game of power or start of dictatorial chapter in the democratic setup.
The people of Punjab felt alienated from main stream due to denial of their just demands during a long democratic struggle since independence. As it happen all over the word, it led to militant struggle with great loss of lives of military, police and civilian personnel. Killing of Indira Gandhi and massacre of innocent Sikhs in Delhi and other India cities was also associated with this movement.
This is a presentation by Dada Robert in a Your Skill Boost masterclass organised by the Excellence Foundation for South Sudan (EFSS) on Saturday, the 25th and Sunday, the 26th of May 2024.
He discussed the concept of quality improvement, emphasizing its applicability to various aspects of life, including personal, project, and program improvements. He defined quality as doing the right thing at the right time in the right way to achieve the best possible results and discussed the concept of the "gap" between what we know and what we do, and how this gap represents the areas we need to improve. He explained the scientific approach to quality improvement, which involves systematic performance analysis, testing and learning, and implementing change ideas. He also highlighted the importance of client focus and a team approach to quality improvement.
How to Make a Field invisible in Odoo 17Celine George
It is possible to hide or invisible some fields in odoo. Commonly using “invisible” attribute in the field definition to invisible the fields. This slide will show how to make a field invisible in odoo 17.
We all have good and bad thoughts from time to time and situation to situation. We are bombarded daily with spiraling thoughts(both negative and positive) creating all-consuming feel , making us difficult to manage with associated suffering. Good thoughts are like our Mob Signal (Positive thought) amidst noise(negative thought) in the atmosphere. Negative thoughts like noise outweigh positive thoughts. These thoughts often create unwanted confusion, trouble, stress and frustration in our mind as well as chaos in our physical world. Negative thoughts are also known as “distorted thinking”.
The Roman Empire A Historical Colossus.pdfkaushalkr1407
The Roman Empire, a vast and enduring power, stands as one of history's most remarkable civilizations, leaving an indelible imprint on the world. It emerged from the Roman Republic, transitioning into an imperial powerhouse under the leadership of Augustus Caesar in 27 BCE. This transformation marked the beginning of an era defined by unprecedented territorial expansion, architectural marvels, and profound cultural influence.
The empire's roots lie in the city of Rome, founded, according to legend, by Romulus in 753 BCE. Over centuries, Rome evolved from a small settlement to a formidable republic, characterized by a complex political system with elected officials and checks on power. However, internal strife, class conflicts, and military ambitions paved the way for the end of the Republic. Julius Caesar’s dictatorship and subsequent assassination in 44 BCE created a power vacuum, leading to a civil war. Octavian, later Augustus, emerged victorious, heralding the Roman Empire’s birth.
Under Augustus, the empire experienced the Pax Romana, a 200-year period of relative peace and stability. Augustus reformed the military, established efficient administrative systems, and initiated grand construction projects. The empire's borders expanded, encompassing territories from Britain to Egypt and from Spain to the Euphrates. Roman legions, renowned for their discipline and engineering prowess, secured and maintained these vast territories, building roads, fortifications, and cities that facilitated control and integration.
The Roman Empire’s society was hierarchical, with a rigid class system. At the top were the patricians, wealthy elites who held significant political power. Below them were the plebeians, free citizens with limited political influence, and the vast numbers of slaves who formed the backbone of the economy. The family unit was central, governed by the paterfamilias, the male head who held absolute authority.
Culturally, the Romans were eclectic, absorbing and adapting elements from the civilizations they encountered, particularly the Greeks. Roman art, literature, and philosophy reflected this synthesis, creating a rich cultural tapestry. Latin, the Roman language, became the lingua franca of the Western world, influencing numerous modern languages.
Roman architecture and engineering achievements were monumental. They perfected the arch, vault, and dome, constructing enduring structures like the Colosseum, Pantheon, and aqueducts. These engineering marvels not only showcased Roman ingenuity but also served practical purposes, from public entertainment to water supply.
The French Revolution, which began in 1789, was a period of radical social and political upheaval in France. It marked the decline of absolute monarchies, the rise of secular and democratic republics, and the eventual rise of Napoleon Bonaparte. This revolutionary period is crucial in understanding the transition from feudalism to modernity in Europe.
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Model Attribute Check Company Auto PropertyCeline George
In Odoo, the multi-company feature allows you to manage multiple companies within a single Odoo database instance. Each company can have its own configurations while still sharing common resources such as products, customers, and suppliers.
Ethnobotany and Ethnopharmacology:
Ethnobotany in herbal drug evaluation,
Impact of Ethnobotany in traditional medicine,
New development in herbals,
Bio-prospecting tools for drug discovery,
Role of Ethnopharmacology in drug evaluation,
Reverse Pharmacology.
Students, digital devices and success - Andreas Schleicher - 27 May 2024..pptxEduSkills OECD
Andreas Schleicher presents at the OECD webinar ‘Digital devices in schools: detrimental distraction or secret to success?’ on 27 May 2024. The presentation was based on findings from PISA 2022 results and the webinar helped launch the PISA in Focus ‘Managing screen time: How to protect and equip students against distraction’ https://www.oecd-ilibrary.org/education/managing-screen-time_7c225af4-en and the OECD Education Policy Perspective ‘Students, digital devices and success’ can be found here - https://oe.cd/il/5yV
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
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
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
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
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
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