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

 

List:

·      Definitions

·      Examples

 

Definitions:

Structural isomerism

·   Same chemical formula, different bond structure

·   Different effects: dihydrocodeine (opioid) and dobutamine (catecholamine)

·   Similar effect: isoflurane and enflurane – volatile anaesthetics

Tautomerism

·   Change in structure dependent upon physical environment

Stereoisomerism

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

-Geometric stereoisomerism

·   Different pairs of chemical groups attached to two carbons joined by a double bond or ring structure

·   Cis = same direction, trans = opposite direction

-Optical stereoisomerism

·   Four different groups attached to a chiral (Gk. hand) centre, usually a carbon or quaternary nitrogen group

·   Four groups point to the vertices of a tetrahedron

·   Two mirror image conformations, not super-imposable

·   Laevo/dextro: enantiomer rotates plane polarized light left/right

·   Rectus/sinister: smallest group ‘behind the page’, three largest groups of the enantiomer arranged in descending order clockwise/anticlockwise

-Diastereoisomerism

·   Multiple chiral centres

 

Structural isomerism example:

 

Isoflurane

Enflurane

Molecular weight

185

185

Boiling point

49

57

Saturated vapour pressure

238

172

MAC

1.2%

1.7%

Blood:gas partition coefficient

1.4

1.8

Fat:blood partition coefficient

45

?

Oil:gas partition coefficient

98

98

% metabolised

0.2

2

Smell

Irritant

Sweet

Analgesic

No

Yes

Epileptogenic

No

Yes

Renal failure

No

Yes

 

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. cisatracurium = 1R-cis,1R’-cis-atracurium

·   15% of atracurium, 50% of its activity

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

·   Cisatracurium: ↑potency, ↓histamine release, ↑Hoffman elimination, ↓ester hydrolysis

 

 

 

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