Isomerism and anesthesia Dr S.Parthasarathy MD., DA., DNB. PhD., FICA., IDRA. Diploma in software based statistics

What is isomerism ? The property of isomerism occurs when two or more compounds have the same atomic formulae, but a different structural arrangement, which often results in different properties. Basic types Structural isomerism Stereoisomerism

Structural isomerism Structural isomers are molecules that have identical chemical formulae, but a different order of atomic bonds. Same actions or different actions Same actions -- anaesthetic volatile agents isoflurane and enflurane Chemical structure Different but configuration same

Different actions- C18H23NO3 dihydrocodeine and dobutamine

Tautomerism Tautomers are organic compounds that are interchangeable by a chemical reaction precipitated by a change in the physical environment.. Keto enol tautomerism of barbiturates Midazolam and ph change

Stereoisomerism- chirality Stereoisomerism describes those compounds which have the same molecular formula and chemical structure, but a different three-dimensional configuration Same chemical structure but different configuration Non superimposable mirror images like left and right hand is chirality Geometric Optical

Chiral centre One carbon or one quaternary N is satisfied with four different chemical groups

Many chiral molecules

Non superimposable mirror image chiral – hand

Geometric isomerism Geometric isomerism or cis-trans isomerism describes the orientation of functional groups within the molecule. Active groups – one side is cis Two sides is trans

Example bromine is active !!

Atra and cis atra

Optical Optical isomers are the same in every way, except being non-superimposable mirror images of each other. They are also called optical isomers because they rotate the plane of polarised light either to the right, referred to as +, dextro, d or D isomer, or to the left, referred to as -, laevo (levo), l or L isomer. – enantiomer Racemic mixture – 1:1 of dextro and laevo

D molecules

More recently, this classification has been replaced by the R or S notation, which describes the arrangement of the molecules around the chiral centre (R is for rectus, the Latin for right, and S for sinister, left).

R S

Chiral switch – drugs Esomeprazole S amlodipine Levocetrizine Levosalbutamol Levodopa Escitalopram S – warfarin

Clinical scenario in anesthesia

Intravenous general anaesthetics Etomidate is unique among intravenous anaesthetics because it is administered as an optically pure R(+) isomer, which is the active component. S(-) thiopentone was found to be about twofold more potent than the R(+) thiopentone in the potentiation of gamma-amino butyric acid (GABA) at GABA A receptors

Ketamine The single S(+) enantiomer of ketamine is two to three times as potent as the R(-) enantiomer and produces less cardiac depression. The S(+) enantiomer does not block myocardial ischaemic preconditioning and causes less intense hallucinations. 

Optical isomerism of ketamine

Dexmed Dexmedetomidine, an imidazole compound, is the pharmacologically active dextro-enantiomer of medetomidine that displays specific and selective alpha 2-adrenoceptor agonism. The central alpha 2-adrenoceptor agonist activity is specific to the dextro enantiomer of medetomidine, thus again utilizing chiral principle

Inhalational agents

Atracurium has four chiral centres in its bis-benzylisoquinolinium structure and the marketed product is a mixture of 10 optical and geometric isomers: three cis–cis, four cis–trans and three trans–trans isomers. Cisatracurium is R-R′ optical isomer of the cis–cis configuration

Gantacurium is a new neuromuscular agent which is metabolized by cysteine But L cysteine hopes to become a promising reversal agent in the future

Local anesthetics Laevobupivacaine appears to cause less myocardial depression than both bupivacaine and ropivacaine, despite being in higher concentrations. Electrophysiological studies have been carried out which demonstrate that blockade of the inactive Na+ channels is stereoselective, with the D isomer being more potent and faster than the L isomer. As this includes the cardiac fibres, it explains the higher cardiotoxicity associated with the D isomer. 

N

Ropi is itself Less motor blockade Less potent Less cardiotoxic Pediatric use

General points Agonist – antagonist Effects – side effects Metabolism and pharmacokinetics the (S, (-)-isomers are more potent but have shorter terminal half lives

Why we need switches ?? 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

They don’t have chiral centres sevoflurane propofol

Summary Isomerism Types Examples Why Clinical uses This is the response to the class