Wk6/7 - medchem epilepsy

What was carbamazepine originally synthesised as?

An antidepressant (analogue of chlorpromazine)

What enzyme metabolises carbamazepine?

CYP3A4

What is the active metabolite of carbamazepine?

10,11-epoxide (active but increases toxicity)

What is the problem with carbamazepine metabolism?

It induces CYP3A4 (autoinducer) → induces its own metabolism → dose adjustments needed

What is oxcarbazepine and why is it safer?

A carbamazepine analogue that is NOT an autoinducer; metabolised to licarbazepine

What is the basic structure of benzodiazepines?

1,4-benzodiazepine with a phenyl substituent at the 5-position

What is essential for the A-ring in benzodiazepines?

Must be aromatic or heteroaromatic for π-stacking; electronegative group at position 7 (NO₂ or Cl) increases activity

What effect do halogens at the 2' position have?

Increase lipophilicity → enhances binding

What is required at position 2 of benzodiazepines?

An H-bond acceptor, co-planar with the aromatic ring

What is the problem with diazepam's metabolism?

Long half-life (2-5 days), forms active metabolite N-desmethyldiazepam, accumulation with repeated dosing

What makes oxazepam better than diazepam?

Short-acting, rapidly excreted via glucuronidation, no active metabolites

How was midazolam designed to have both water and lipid solubility?

pKa 6.2 – water-soluble at pH3 (formulation), ring closes at pH7 (body) to become lipid-soluble

What is 1,2-annelation in benzodiazepines?

Extending the ring system (adding triazole or imidazole) to block metabolism at N-1 – examples: triazolam, midazolam

How was valproate discovered?

Serendipitously – used as a solvent for khellin derivatives, but the solvent itself was the active agent

What is the active species of valproate at physiological pH?

Sodium valproate (completely ionised)

What metabolite of valproate causes hepatotoxicity?

4-ene valproic acid

What is DP-VPA?

A phospholipid prodrug of valproic acid activated by phospholipase A2 (raised in epilepsy)

What is vigabatrin's mechanism?

Irreversible suicide inhibitor of GABA transaminase (GABA-T)

Is vigabatrin active before metabolism?

No – it is inactive until processed by its target enzyme

How does vigabatrin cross the BBB?

Electron-withdrawing group reduces pKa of the amine, making it more lipophilic

How does gabapentin cross the BBB?

Via the L-amino acid transporter (LAT1) – same as L-DOPA

Is gabapentin a GABA agonist?

No – it works on P/Q-type Ca²⁺ channels

How much more potent is pregabalin than gabapentin?

3-10x more potent

Why is it bad to co-administer valproic acid and carbamazepine?

Both affect CYP enzymes → drug interactions → altered levels → toxicity or loss of efficacy