GABA/Glutamate

Question 1

glutamic acid decarboxylase (GAD)

Answer 1

Glutamate is decarboxylated to GABA process mediated by glutamic acid decarboxylase (GAD) in GABAergic nerve terminals—Inhibited by allylglycine

Question 2

What does GAD (glutamic acid decarboxylase) require as a cofactor?

Answer 2

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.)

Question 3

VGAT

Answer 3

GABA is packaged into storage vesicles by transporter VGAT

Question 4

Tiagabine

Answer 4

Tiagabine is a competitive inhibitor of GAT-1 (used for epilepsy-anticonvulsants)
You’re basically inhibiting the transporter= encouraging GABA to stay, encouraging inhibition

Question 5

GABA-transaminase (GABA-T)

Answer 5

regenerates glutamate from α-ketoglutarate (a product of GABA going through krebs cycle)

Question 6

Vigabatrin

Answer 6

Vigabatrin inhibits GABA-T (used as an anticonvulsant—inhibits enzyme that converts GABA to glutamate. Potentiates GABA effects bc not broken down)

Question 7

What are the 2 types of GABA receptors?

Answer 7

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.

Question 8

GABA agonists

Answer 8

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

Question 9

Benzodiazepines

-PAM

Answer 9

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

Question 10

CYP3A4 for metabolizes which GABA drugs?

Answer 10

Benzodiazepines (all end in -PAM)

Question 11

WHat are benzodiazepines used for?

Answer 11

Used as sleep enhancers, anxiolytics, sedatives, antiepileptics, muscle relaxers, and for the treatment of alcohol withdrawl

Question 12

What is an antagonist/antidote for benzodiazepines?

Answer 12

Flumazenil

Question 13

Barbiturates

Answer 13

GABA agonists: Butabarbital, Butalbital, Methohexital, Pentobarbital, Primidone, Secobarbital, Thiopental

Question 14

What are some effects of barbiturates?

Answer 14

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

Question 15

Anesthetic Barbiturates

Answer 15

Thiopental, pentobarbital and methohexital

Act as agonists at GABA-A and enhance the receptors response to GABA at allosteric site. Do both.

Question 16

Anticonvulsant Barbiturates

Answer 16

Phenobarbital (no direct agonism at GABAa. Not same amt of sedation as w/ anesthetic barbiturates)

Question 17

What is one of the biggest groups of P450 inducers?

Answer 17

Barbiturates.
Metabolism makes them work better. Contributes to tolerance. Barbituates induce their own metabolism so trickier to dose long-term

Question 18

Etomidate and Propofol

Answer 18

Enhance activation of GABA-A by GABA and at high doses act as agonists.
Induce anesthesia in high enough doses (and conscious sedation)

Question 19

Baclofen

Answer 19

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)

Question 20

Ethanol

Answer 20

Multiple targets including GABA-A and glutamate receptors

Question 21

Gamma hydroxybutyric acid (GHB)

Answer 21

“date rape” drug. GABA isomer clinical use for narcolepsy

Question 22

AMPA and Kainate

Answer 22

Ionotropic glutamate receptors. Throughout CNS (hippocampus, cerebral cortex)
Activation results in Na influx and K efflux
Possible Ca permeability

Question 23

NMDA

Answer 23

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)

Question 24

Excitotoxicity

Answer 24

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

Question 25

Riluzole, Memantine, Amantadine

Answer 25

NMDA antagonists (block glutamate receptor—blocking excitation)

Question 26

Which drug blocks Na channels thereby decreasing glutamate plus acts as an NMDA antagonist?

Answer 26

Riluzole

Question 27

What are the non- competitive blockers of NMDA?

Answer 27

Memantine-Alzheimers

Amantadine- Decreases dyskinesia in Parkinson’s disease

Question 28

Lamotrigine

Answer 28

Stabilizes inactivated state of Na channel reducing excitability and glutamate release- seizures

Question 29

Felbamate

Answer 29

One mechanism inhibit NMDA receptors- seizures

Question 30

GABA vs Glutamate

Answer 30

GABA-inhibitory

Glutamate- excitatory

Question 31

allylglycine

Answer 31

inhibits the synthesis of GABA

Question 32

isoniazid pyridoxal kinase

Answer 32

Used to treat tuberculosis. HAS ANTI-B6 EFFECTS. You’ll have too much glutamate, not enough GABA= excitation issues unless you supplement with B6

Question 33

What inhibits the release of GABA after its been synthesized?

Answer 33

tetanus toxin