GABA/Glutamate Flashcards
(33 cards)
glutamic acid decarboxylase (GAD)
Glutamate is decarboxylated to GABA process mediated by glutamic acid decarboxylase (GAD) in GABAergic nerve terminals—Inhibited by allylglycine
What does GAD (glutamic acid decarboxylase) require as a cofactor?
GAD requires pyridoxine (vitamin B6) as a cofactor.
(Isoniazid pyridoxal kinase (anti B6 effect)—used to treat tuberculosis. Will have problems with too much excitation unless you supplement vitB6.)
VGAT
GABA is packaged into storage vesicles by transporter VGAT
Tiagabine
Tiagabine is a competitive inhibitor of GAT-1 (used for epilepsy-anticonvulsants)
You’re basically inhibiting the transporter= encouraging GABA to stay, encouraging inhibition
GABA-transaminase (GABA-T)
regenerates glutamate from α-ketoglutarate (a product of GABA going through krebs cycle)
Vigabatrin
Vigabatrin inhibits GABA-T (used as an anticonvulsant—inhibits enzyme that converts GABA to glutamate. Potentiates GABA effects bc not broken down)
What are the 2 types of GABA receptors?
Inotropic GABA receptors (GABA-A and GABA-C)
Binds GABA and opens an intrinsic chloride ion channel
Metabatropic GABA receptors (GABA-B)
G protein-coupled receptors that affect neuronal ion currents through second messengers.
GABA agonists
Muscimol (from poisonous mushrooms. Directly binds GABA-a) and Gaboxadol (not drugs used medicinally—just in lab animals) bind directly to GABA binding site of GABA-A receptors
Benzodiazepines
Barbiturates are modulators of GABA-A receptors binding to allosteric sites to enhance GABAergic neurotransmission
Benzodiazepines
-PAM
GABA agonists: Midazolam, Diazepam, Alprazolam, Chlorazepate, Lorazepam, Chlordiazepoxide, Clonazepam, Flurazepam, Temazepam, Triazolam, Zolpidem
Do not activate receptor in absence of GABA, Potency is correlated to hydrophobicity (d/t BBB)
Highly protein bound
CYP3A4 for metabolizes which GABA drugs?
Benzodiazepines (all end in -PAM)
WHat are benzodiazepines used for?
Used as sleep enhancers, anxiolytics, sedatives, antiepileptics, muscle relaxers, and for the treatment of alcohol withdrawl
What is an antagonist/antidote for benzodiazepines?
Flumazenil
Barbiturates
GABA agonists: Butabarbital, Butalbital, Methohexital, Pentobarbital, Primidone, Secobarbital, Thiopental
What are some effects of barbiturates?
Affect CNS sites in spinal cord, brainstem, and the brain.
Cause sedation, amnesia, and loss of consciousness by affecting GABA receptors in the brainstem (used as sedative hypnotics—like prior to surgery)
Spinal cord- relaxes muscles and suppresses reflexes
Anesthetic Barbiturates
Thiopental, pentobarbital and methohexital
Act as agonists at GABA-A and enhance the receptors response to GABA at allosteric site. Do both.
Anticonvulsant Barbiturates
Phenobarbital (no direct agonism at GABAa. Not same amt of sedation as w/ anesthetic barbiturates)
What is one of the biggest groups of P450 inducers?
Barbiturates.
Metabolism makes them work better. Contributes to tolerance. Barbituates induce their own metabolism so trickier to dose long-term
Etomidate and Propofol
Enhance activation of GABA-A by GABA and at high doses act as agonists.
Induce anesthesia in high enough doses (and conscious sedation)
Baclofen
GABA-B agonist
Used primarily for treatment of spasticity associated with motor neuron diseases (and muscle relaxant)
No tolerance when admin orally. Severe when admin intrathecally.
Withdrawal (esp from intrathecal) can precipitate acute hypersensitivity, rhabdomyolysis, pruritis, delerium, and fever (can be a fatal withdrawal if not treated)
Ethanol
Multiple targets including GABA-A and glutamate receptors
Gamma hydroxybutyric acid (GHB)
“date rape” drug. GABA isomer clinical use for narcolepsy
AMPA and Kainate
Ionotropic glutamate receptors. Throughout CNS (hippocampus, cerebral cortex)
Activation results in Na influx and K efflux
Possible Ca permeability
NMDA
Ionotropic glutamate receptor. (most of our drugs affect this receptor)
Primarily hippocampus, cerebral cortex, and spinal cord
Activation requires simultaneous binding of 2 things:glutamate as well as glycine
Response is to open a channel that allows K efflux, Na and Ca influx
Channel occupied by both glutamate and glycine are blocked by Mg ions in resting membrane (requires depolarization (by activating AMPA and KAINATE) to remove Mg block)
Excitotoxicity
Increased release or decreased reuptake of glutamate results in increased intracellular Ca, cellular damage, and further glutamate release (positive feedback—overall damage If you don’t have inhibitory GABA to shut it off)
Implicated in neurodegenerative diseases, stroke, trauma, hyperalgesia, and epilepsy
