Pharmacology - Isomerism

Question 1

What is isomerism?

Answer 1

Isomers are molecules with the same chemical formula, but a different arrangements of atoms in space

They might be structural (static or dynamic), or stereoisomers (geometric or optical)

This can form two molecules with similar properties:
Osoflurane & enflurane

Or very different properties:
Prednisolone & aldosterone
Dihydrocodeine & dobutamine

Drugs such as sevoflurane and propofol are examples that do NOT demonstrate isomerism

Question 2

What are structural isomers?

IMAGE Enflurane vs Isoflurane, Tautomerism, Midaz

Answer 2

Molecules with the same chemical formula, but not the same structure, which may be static or dynamic

Static
Positional - Atoms occupying different positions on an identical carbon chain - such as isoflurane & enflurane (both have similar oil:gas partition coefficients of 99 and 98 respectively)

Chain - Different carbon skeletons - such as pentane & isopentane, but the same functional groups

Functional group - Different functional coups, such as methyl-ethyl ether and propanol

Dynamic
Tautomerism of thiopental
Solube, ionised thiopental exists at an alkaline pH. The pH drop when injected into the plasma causes the molecule to unionise into the thiol group, and then rapidly convert to the pharmacologically active thipentone.

pH dependent ring closure of midazolam
Primary amine group is ionised in low pH environments (below pH 4) (so is water soluble), in the blood, a pH dependent ring closure occurs, forming a benzodiazepine ring, which is unionised and lipid soluble.
The pKa of midazolam is 6.5, so approximately 90% is unionised in the blood.

Question 3

What are stereoisomers?

IMAGE - Geometric vs Enantiomers

Answer 3

Molecules with the same chemical formula, and same broad structure, but different arrangement in space. May be geometric (cis-trans), or optical (enantiomers)

Geometric
Rely on a carbon-carbon double bond (or ring), which is unable to rotate. The differing groups may be arranged either diagonally opposing (trans), or on the same side (cis) of the bond, resulting in different conformation & chemical behaviour.

Mivacurium exists as three possible geometric isomers due to having two sites of isomerism.
Trans-trans (58%)
Cis-trans (36%)
Cis-cis (6%)

Optical
Molecules with a tetravalent chiral centre. A carbon (or nitrogen) molecule bound to 4 different groups, where differing arrangement creates different molecules which cannot be superimposed.
Previously categorised based on ability to deflect plane-polarised light (levo deflected leftwards, dextro deflected rightwards)

Modern classification uses R and S instead.

Examples are:
Warfarin, ropivacaine, bupivacaine, halothane, isoflurane, etomidate, ketamine, thalidomide

“Imagining the atom with the lowest atomic number lies behind the plane of the page, the other three atoms will lie in the plane of the page. In the ‘R’ enantiomer, the atomic numbers descend in a clockwise manner. If the atomic numbers descend in an anti-clockwise manner, the enantiomer is the ‘S’ form” - Blandford

Question 4

What are diastereoisomers?

Answer 4

Some molecules have more than one chiral centre, as such, the multiple configurations are not all mirror images of each other

A molecule with X chiral centres will have X² possible diastereoisomers, but due to internal symmetry, some may be duplicates.

Atracurium has 4 chiral centres, but only 10 formations.

Cisatracurium (R’cis-R’cis) does not cause histamine release, and produces less laudanosine, with a similar duration of action. It is also degraded by Hofmann elimination to laudanosine & a monoquaternary acrylate. It is more 3-4x potent than atracurium, but still relatively slow in onset.

Question 5

What is a racemic mixture?

Answer 5

A mixture of isomers in equal proportion
Isoflurane
Ketamine (May also be produced as enantiopure esketamine)
Adrenaline
Warfarin
Bupivacaine (Dextrobupivacaine is much more cardio- and neuro-toxic than levobupivacaine, and is responsible for most of the toxicity in the racemic mixture)

Molecules produced naturally tend to exist as single isomers, as the enzyme producing them can only produce that conformation. Artificially synthesied molecules often have racemic mixtures as a result of purification processes.