GABA and Benzodiazepines

  • Created by: LBCW0502
  • Created on: 23-10-18 18:30
Describe features of benzodiapizines (1)
1930s (Sternbach, Pharmacist PhD Chemistry). Synthetic dyes heptoxadiazines. 1954 (Hoffman La Roche New York). Chlopromazine. Heptoxadiaxine (psychopharmacological activity), 40 compounds - none active
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Describe features of benzodiapizines (2)
Chlropromazine left on shelf - formation of Ro-5-0690. Identified as first benzodiazepine in 1960.
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Outline the mechanism for the formation of chlordiazepoxide
Nucleophilic addition using secondary amine. Elimination reaction
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Describe various drugs within the class of benzodiazepines (1)
Chlordiazepoxide (tranquilliser, anti-anxiety agent hypnotic, dependence/tolerance with prolonged use). Diazepam (muscle relaxant properties, t1/2 of 24-28h, clearance 2-5 days, accumulation, Nordiazepam).
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Describe various drugs within the class of benzodiazepines (2)
Oxazepam (metabolite of diazepam). Lorazepam/Temazepam (hypnotic, t1/2 8h). Flunitrazepam. Midazopam (only one water soluble, t1/2 1-3h, amnesia 10min after administration, IV/sedation in ICU)
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What is GABA?
4-aminobutyric acid. Formed from glutamine. Acts as an inhibitory neurotransmitter. Broken down in synaptic cleft by GABA-T
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Outline the biosynthesis of GABA
Glutamine - Glutamate - (GAD/PLP) - GABA - (PLP) - Succinic semi-aldehyde - GHB and succinic acid
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Give three examples of rationally designed anticonvulsants
Vigabatrin, Gabapentin, Pregabalin/Lyrica
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Outline the mechanism for imine formation
Nucleophilic attack of amine on carbonyl. Protein transfer (x2). Formation of good leaving group (weak base). Removal of leaving group. Removal of water shifts equilibrium. Proton transfer. Formation of imine
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Describe the mechanism for PLP bound to an enzyme and GABA
GABA amino group displaces enzyme amino group on PLP. Base on enzyme accepts proton. Protonation. Use of water. Release of succinic semi-aldehyde. Break down GABA using GABA-T
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Describe the mechanism for PLP bound to an enzyme and a drug molecule
Vinyl GABA amino group displaces enzyme amino on PLP. Base on enzyme removes proton. Enzyme attacks conjugated alkene. Irreversible inhibition of enzyme (substrate-enzyme-cofactor, covalent bond) - inhibit GABA-T
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What is vigabatrin used for?
Irreversibly binds GABA-T, prevents GABA catabolism. Given to patients with partial epilepsy who don't respond to other drugs
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What is baclofen used for?
Agonist binds to GABA-B receptors. Relaxes skeletal muscles. Used in multiple sclerosis and spinal disease. Higher doses sedative effect
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Describe features of the discovery of Lyrica (1)
Evaluate compounds (weak anticonvulsant). Test 3-isobutyl GABA compounds (nearly complete protection in mice from seizures)
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Describe features of the discovery of Lyrica (2)
Lyrica. Anticonvulsant activity (not related to GAD activation). No correlation, GAD activation and 3-alkyl GABA and anticonvulsant activity. 3-alkyl GABA, GABApentin activates GAB
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Describe features of the discovery of Lyrica (3)
GABApentin selectively binds to a2 sigma subunit of Ca 2+ channel. Inhibits release of SP and glutamate from excitatory AA nerve terminals. Lowering excitatory neurotransmitter accomplishes the same objective as raising inhibitory neurotransmitter
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Describe features of the discovery of Lyrica (4)
3-isobutyl GABA and 3-alkyl GABA are substrates for system S transporter. Actively transported into brain. Substrate L-leucine. Refractory partial onset seizures (150-600 mg/day). Postherpetic neuralgia (shingles). Neuropathetic pain/diabetes 300 mg
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Card 2

Front

Describe features of benzodiapizines (2)

Back

Chlropromazine left on shelf - formation of Ro-5-0690. Identified as first benzodiazepine in 1960.

Card 3

Front

Outline the mechanism for the formation of chlordiazepoxide

Back

Preview of the front of card 3

Card 4

Front

Describe various drugs within the class of benzodiazepines (1)

Back

Preview of the front of card 4

Card 5

Front

Describe various drugs within the class of benzodiazepines (2)

Back

Preview of the front of card 5
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