2013C03 Classify isomers. Briefly write an account of their significance in drugs used in anaesthesia.

 

List:

·     Definitions

·     Examples

 

Definitions:

Isomerism

·   Same chemical formula, different arrangement of atoms

Structural isomerism

·   Same chemical formula, different bond structure

-Tautomerism

·   Change in bond structure is dependent upon physical environment

Stereoisomerism

·   Same chemical formula, same bond structure, different 3D orientation

-Geometric type

·   Different pairs of chemical groups are attached to C=C or a ring structure

·   Cis = groups on same side, trans = groups on opposite side

·   Results in multiple conformations that may or may not be superimposable

-Optical type

Description:

·   Four different groups attached to a chiral centre, usually a C or quaternary N group

·   Four groups point to the vertices of a tetrahedron

·   Results in two mirror image conformations

Nomenclature:

·   Laevo/dextro: molecule rotates plane polarized light left/right (hence ‘optical’)

·   Rectus/sinister: smallest group ‘behind the page’, three largest groups of the molecule arranged in descending order clockwise/anticlockwise
(aide-memoire: imagine right/left handed screwdriver for rectus/sinister respectively)

Stereoisomers

 

-Enantiomers

·   Two molecules that are mirror-image stereoisomers;
they are not superimposable

·   These can have any number of stereocentres (chiral or geometric)
(but classically just one optical sterocentre)

-Diastereoisomers

·   Two or more molecules that are non-mirror image stereoisomers;
they may be superimposable

·   These have multiple stereocentres (chiral or geometric)

 

Structural isomerism examples:

Different effects

·   Dihydrocodeine (opioid)

·   Dobutamine (catecholamine)

Similar effects

·   Isoflurane (anaesthetic – MAC 1.2%, 0.2% metabolised, irritant)

·   Enflurane (anaesthetic – MAC 1.7%, 2% metabolised, sweet smell)

 

Tautomerism examples:

Midazolam

·   Ampoule: pH<4 -> open ring, water soluble, no carrier needed

·   Blood: pH >4 -> closed ring lipid soluble, crosses blood-brain barrier (BBB)

Thiopentone

·   Ampoule: ↑pH (11)-> water soluble enol

·   Blood: ↓pH 7.4 -> lipid soluble keto -> crosses BBB

 

Stereoisomerism examples:

Geometric

e.g. mivacurium

·   Cis-cis 6% (10% potency of others, non-enzymatic metabolism, t1/2 10x others)

·   Cis-trans 36%

·   Trans-trans 58%

Optical

Laevo/dextro:

·   e.g. D-glucose metabolized, L-glucose not (i.e. dextrose)

·   e.g. L-bupivacaine ↑potent, ↓toxic (available enantiopure)

·   e.g. +tramadol mu agonist, 5-HT reuptake inhibition; -tramadol NAd reuptake inhibition

·   e.g. L-methadone opioid agonist, D-methadone NMDA antagonist

Rectus/sinister:

·   e.g. S-ketamine ↑potency, ↓hallucinogen, ↓CVS toxicity; (available enantiopure)

·   e.g. R-etomidate 10x ↑potent (only available enantiopure)

Diastereoisomerism

e.g. atracurium

·   Exhibits both geometric and optical stereoisomerism within the molecule
(however no mirror images between molecules, i.e. it does not have enantiomers)

·   4 chiral centres; n2 = 16 conformations; but only 10 are unique

·   Geometric isomer groups designated cis-cis, cis-trans and trans-trans according to configuration about the tetrahydroisoquinolinium ring

·   Cisatracurium = 1R-cis,1R’-cis-atracurium

o   ↑Potency (15% of the molecules, 50% of the activity)

o   ↑Hoffman elimination, ↓ester hydrolysis

o   ↓Histamine release

 

 

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