Pharm - Isomers

Question 1

What is an isomer?

Answer 1

Molecules with the same molecular formula but whose atoms are arranged differently

Question 2

Can you classify isomers?

Answer 2

Structural isomers:
- Chain
- Functional
- Position

Stereoisomers:
- Enantiomers
- Cis/Trans

Question 3

What is a structural isomer?

Answer 3

Same molecular formular but bonds are arranged differently.

Chain isomers: carbon skeleton varies but functional group is in the same position

Positional isomers: carbon skeleton is the same but functional group varies position

Functional isomers: carbon skeleton is the same but functional group changes (enflurane and isoflurane)

Tautomers: Dynamic isomerism where two structural isomers exist in equilibrium (midazolam, thiopentone, morphine)

Midazolam: seven membered ring - at pH <4 ring is open and the molecules are water soluble. At pH>4 ring closed and molecules lipid soluble

Thiopentone and morphine exist in keto and enol forms.

Question 4

What are stereoisomers?

Answer 4

Same molecular and chemical structure but different spatial arrangements

Enantiomers and diastereoisomers (i.e. optical isomers)

Cis-trans isomers (i.e. geometric isomers)

Enantiomers:
1. single carbon centre e.g. carbon or nitrogen. In enantiomers, the four surrounding bonds form mirror images but cannot be superimposed on each other
2. They have similar physical and chemical properties
3. They rotate polarised light equally but in opposite directions, leading to the older nomeclature laevo (left) and dextro (right)
4. Now they are classified by the order of attached atoms in ascending molecular weight. Clockwise would be R (rectus), anticlockwise would be S (sinister)
5. Examples: Levobupivicaine and bupivicaine, ketamine and S-ketamine

Diastereoisomers: possess more than one chiral centre e.g. atracurium has four chiral centres

Cist-trans (formerly geometric):
1. Possess a double bond so that attached atoms cannot rotate
2. Cis form - the groups are arranged on the same side of the double bond, trans - the groups are arranged diagonally
3. It only works if the two groups are identical
4. E.g. mivacurium 36% is cis-trans, 58% is trans-trans, 6% is cis-cis

Question 5

Give some clinical examples of isomerism

Answer 5

• Comparing S-ketamine with racemic ketamine, S-ketamine has greater affinity for the NMDA receptor, it is twice as
  potent, patients report a more pleasant experience at doses causing the same effect and recovery of mental function is quicker.
• Comparing esomeprazole with omeprazole, it has higher bioavailability.
• Comparing S-warfarin with R-warfarin, it is more highly protein bound, its volume of distribution is lower, it is more potent and its half-life is only 32 hours compared to 54 hours for R-warfarin.
• Halothane, enflurane and isoflurane are chiral isomers with differing anaesthetic potency.
• Sotolol is formulated as a racemic mixture but only the L-isomer has any beta-blocking activity.
• Some isomers are unsafe for clinical use, e.g. R-thalidomide is sedative
  while S-thalidomide is teratogenic; L-dopa is used to treat Parkinson’s
  disease, while D-dopa is not because it causes neutropenia.