Lecture 8 Flashcards
What is the inhibitory neurotransmitter?
GABA
What is the excitatory neurotransmitter?
Glutamate
What mediates the decarboxylation of glutamate to GABA?
Glutamic acid decaroxylase (GAD)
What inhibits the decarboxylation of glutamate to GABA?
Allylglycine (convulsant)
What vitamine is required by GAD as a cofactor?
Pyridoxine (vitamin B6)
What packages GABA into storage vesicles?
VGAT
What inhibits GABA release into synaptic cleft?
Tetanus toxin
The neurons and glia take up GABA via _________________.
GABA transporters (GATs)
What is a competitive inhibitor of GAT-1 and is used for epilepsy?
Tiagabine
What inhibits GABA-T? used as an antivonvulsant.
Vigabatrin
What are the 2 types of GABA receptors?
Iontropic (GABA A and GABA C)
Metabatropic (GABA B)
What type GABA receptor binds GABA and opens an intrinsic chloride ion channel?
Inotropic GABA receptors (GABA A and C)
What type GABA receptor is G-protein couples and affects neuronal ion currents via second messenger?
Metabatropic GABA receptors (GABA b)
The activation of GABAa requires the binding of how many molecules of GABA?
2, one to each agonist site
All of these (Pregnenolone, DHEA, DHDOC, THDOC, oleamide) are neurosteroids that modulate GABAa by binding to _____ sites on the receptor and cause increased reception activation.
Allosteric
What are 2 drugs that bind directly to GABAa receptors?
Muscimol and gaboxadol
What are 2 drug classes that are modulators of GABA a receptors and bind to allosteric sites to enhance GABAergic neurotransmission.
Benzodiazepines
Barbiturates
What suffix do benzodiazepines typically end in?
Pam
exception- triazolam, zolpidem
Do benzodiazpeines activate a receptor in the absence of GABA?
nope
Are benzodiazepines bound to protein usually?
Yes- highly protein bound
What is the potency of benzodiazepines correlated to?
Hydrophobicity
What metablizes benzodiazepines?
CYP3A4
What is an ADR of benzos?
amnesia
When can benzos cause death?
When combined with alcohol (CYP3A4 inhibitor and CNS depressant)
What is an antagonist of benzos?
Flumazenil
What are some uses of benzos?
sleep enhances anxiolytics sedatives antiepileptics muscle relaxers treatment for alcohol withdrawal
What suffix do barbiturates usually end with?
“tal”
What CNS sites do barbiturates affect?
spinal cord
brain stem
brain
What do barbiturates do?
Sedation
Amnesia
Loss of consciousness by affecting GABA receptors in the brain
What are these barbiturates used for?
Thiopental, pentobarbital, methohexital
Anesthetic barbiturates
Act as agonists at GABA a
What are is a barbiturates used as anticonvulsants?
Phenobarbital
less direct agonism
What does the termination of barbiturates effects depend primarily on?
Redistribution from CNS to highly perfused areas
What happens with chronic use of barbiurates?
High uptake into adipose tissue and there is a longer elimination 1/2 life
What metabolizes barbiturates?
Hepatic metabolism, P450
What 2 drugs enhance the activaiton of GABA a by GABA and at high doses act as agonists? They also help induce anesthesia.
Etomidate
propofol
Where are most GABA B receptors found?
Spinal cord
What is a GABA B agonist that is used primarily for treatment of spasticity associated with motor neuron diseases. Can be administered orally in mild cases and intrathecal in severe cases.
Baclofen
Can withdrawl occur with baclofen?
yes, can result in acute hypersensitivty, rhabdomyolysis, pruritis, delerium and fever. Especially found with intrathecal route
What targets does Ethanol have?
GABA A and glutamate receptors as well as others
What is a GABA isomer clinically used for narcolepsy?
Gamma hydroxybutyric acid (GHB)
What are the 2 pathways for glutamate synthesis?
- Product formed in Kerbs cycle is transaminated to glutamate
- Glutamien produced in glial clles can enter Krebs cycle and converted to glutamate in nerve terminal
How is glutamate terminated?
REuptake transporters take glutamate up and plutamine synthetase converts glutamate into glutamine
What are the 3 inotropic glutamate receptors?
AMPA
Kainate
NMDA
What 2 glutamate receptors are foudn throughout the CNS and activation results in NA influx and K efflux (possible Ca permeability)
AMPA and Kainate
What inotropic glutamate receptor is foudn primarily in hippocampus, cerebral cortex and spinal cord. Requires binding of glutamate and glycine for activation and then allows for K efflux, Na and CA influx. Requires a depolorization to remove Mg block
NMDA
What type of metabotropic glutamate receptor causes neuronal excitation through phospholipase C activation?
Group I
What 2 types of metabotropic glutamate receptors work by inhibiting adenyl cyclase and decrease cAMP production?
Group II and Group III
What can happen with too much glutamate release or decreased reuptake?
Increased intracellular Ca resulting in cellular damage and further glutamate release
What are some conditions where you see excitotxicity?
Stroke
Trauma
Hyperalgesia
Epilepsy
What are 3 NMDA agntagonists?
Riluzole
Memantine
Amatadine
What NMDA antagonist works by blocking Na channels and decreasing glutamate
Riluzole
What 2 NMDA antagonists are non-competitive blockers of NMDA?
Memantine and Amatadine
What NMDA antagonist is used in Alzheimers?
Memantine
What NMDA antagonist is used in Parkinson’s to decrease dyskinesia?
Amatadine
What is an drug that stabilizes inactivate state of Na channel reducing excitability and glutamate release-seizures?
Lamotrigine
What is a drug that inhibits NMDAs and is used in seizures?
Felbamate
