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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