Chapter 12: GABA/Glutamate Flashcards
What ions are induced in what direction by inhibitory neurotransmitters?
K+ efflux, Cl- influx, close Ca+2 channels
What ions are induced in what direction by excitatory neurotransmitters?
Na+ influx, Ca+2 influx, close K+ channels
What amino acid is GABA made from, and what is the enzyme & cofactor that forms it?
glutamate –(GAD aka Glutamic Acid Decarboxylase + vit B6)–> GABA
What does GABA get broken down to and by what enzyme?
–(GABA-transferase)–> succinic semialdehyde–>succinic acid
What is reformed in the Krebs cycle to make more GABA, and by what enzyme?
–(GABA-transferase)–> alpha-ketoglutarate
Name the 5 main substrates of the GABA cycle, from what is the 1st “ingredient” to the last breakdown product
- alpha-ketoglutarate
- glutamate
- GABA
- succinic semialdehyde
- succinic acid (–> go to Krebs cycle and reform #1)
What is the GABA(A) receptor made of, and what does it let in?
two alpha, two beta, and one gamma subunit. Lets in Cl- thru central pore when GABA binds to 2 sites
What is different about GABA receptors in neonates?
The Cl- gradient is reversed (Cl- EFFlux instead), causing DEpolarization instead of hyperpolarization. This means drugs that work on GABA in neonates will have EXCITATORY effect instead of inhibitory!
What effect does increasing concentrations of GABA have on channel conduction?
Induce greater Cl- currents and more rapid receptor densensitization (so, increase both “strength” and “speed”)
What effect do do oleamide (fatty acid amide found in sleep deprived animals) and neurosteroids deoxycorticosterone and progesterone have on GABA?
Cause increased GABA receptor activation
Where is GABA(c) found?
retina
Where is GABA(B) found, and what channels does it act on?
spinal cord.
activates K+ channels, inhibits Ca+2 channels
What two receptors does ethanol act on?
GABA(A) (increasing Cl- influx) and NMDA (inhibiting glutamate effects)
What drug alleviates insomnia and incapacitates individuals against their will?
chloral hydrate
What two drugs are abused for “date rape”?
gamma hydroxybutyric acid (supposed to be for narcolepsy)
- flunitrazepam (for amnesia)
If it is not recycled from the Krebs cycle, what else can glutamate be synthesized from, and from what cells?
glutamine, from glial cells
What are the three main subtypes of inotropic glutamate-gated ion channels, and what ions do they permit?
1) AMPA (Na+ influx)
2) kainate receptors (Na+ influx, K+ efflux)
3) NMDA (Na+ & Ca+2 influx, K+ efflux)
What do you need to bind to open NMDA receptors, and what block will be taken off by depolarization?
need simultaneous glycine & glutamate binding; will relieve Mg+2 block
What are the functions of the 3 main groups of metabotropic glutamate receptors ?
Group I: EXCITATION:increases PLC and increases cAMP.
Group II & III: INHIBITION: decreases cAMP
Elevated glutamate in what diseases/conditions?
Huntington’s, ALS, Alzheimer’s, ischemic stroke, traumatic brain injury, hyperalgesia (probs), epilepsy
What is the mechanism by which glutamate elevation in stroke and trauma lead to neuronal cell death?
Ca+2 influx activates Ca+2 dependent degradation enzymes (DNAses, proteases, PLases, etc)
What is the pathogenesis of hyperalgesia?
central sensitization: repeated stimuli increase excitatory postsynaptic responses (more Ca+2 allowed to enter thru AMPA receptors)
What oral drug treats focal and tonic-clonic seizures by inhibiting GAT-1 which increases presynaptic GABA, has hepatic metabolism, and can cause confusion, sedation, and dizziness?
tiagabine
What drug treats focal and topic-clonic seizures by inhibiting GABA transferase, but has serious side effects of retinal atrophy and angioedema?
vigabatrin
What experimental drug directly activates GABA(A) receptors and is derived from the Amanita muscaria mushroom?
Muscimol
What experimental drug binds to alpha4, beta3, and delta GABA subunits at low doses possibly for insomnia, and is a partial agonist at general GABA(A) receptors at high doses?
gaboxadol
What experimental drug is a COMPETITIVE antagonist of GABA(A), therefore promoting convulsions
bicuculline, gabazine
What experimental drug is a NONCOMPETITIVE antagonist of GABA(A), therefore promoting convulsions
picrotoxin
What is the difference in mechanism of benzodiazepines vs. barbituates?
benzos: increase the FREQUENCY of GABA(A) receptor opening.
barbs: enhance GABA activity, increasing the TIME GABA(A) receptors are left open. Also antagonizes AMPA (decreasing glutamate)
What are side effects of benzodiazepines?
respiratory depression, desaturation in pediatric patients, somnolence, headache, fatigue, impaired hepatic function (met. by P450 3A4), death if taken with alcohol
What is the best treatment mentioned for absence seizures?
Clonazepam
What is a benzo used for amnesia induction during acute care?
midazolam
What drugs are used for anxiety?
alprazolam, diazepam (more benzos, but these were mentioned most)
What class of drugs can be used for alcohol withdrawal?
benzodiazepines
What drugs are used for insomnia and what effect do they have that makes sleep ‘abnormal’?
triazolam, flurazepam (72 hr 1/2 life = sleepiness duraction) + more less mentioned benzos.
Via increasing non-REM sleep, decreasing REM and slow wave sleep
What competes with benzos for sites on GABA(A) receptors to reverse their activity, but can cause severe withdrawal?
flumazenil
What are the short acting benzos?
clorazepate, triazolam, midazolam, zopidem (“C TMZ” = cunts at TMZ gets pics of celebs the fastest)
What drugs can decrease benzo levels?
carbamazepine, phenobarbital
What is the main use of methohexital, pentobarbital, and thiopental
induction and maintenance of anesthesia
What are the main side effects of barbiturates?
HEPATOXICITY(b/c hepatic metabolism), respiratory depression, hypnosis, coma, death, “EEG silence”, drug withdrawal symptoms, Steven Johnson sydrome
What increases urinary clearance of barbiturates?
administration of NaCO3
What are the contraindications of barbiturates?
the elderly, people with liver problems
What barb is best for refractory epilepsy, especially focal and tonic-clonic seizures?
phenobarbital
What drugs enhance activation of GABA(A) receptors at the beta2 and beta3 subunits, are fast acting with hepatic metabolism, induce anesthesia, and have bad side effects of CV and resp. depression?
etomidate, propofol
What drug induces anesthesia but not maintenance (esp for hemodynamically unstable patients) and treats cortsol producing tumors (thus should be administered with glucocorticoids)?
etomidate
What drug induces AND maintains anesthesia, is useful in short day surgery, and is a lipid emulsion so causes hyperlipidemia?
propofol
What neuroactive steroid used experimentally enhances GABA(A) receptor activation and is more potent with delta?
alphaxalone
What oral drug activates the GABA(B) receptor by stimulating secondary messengers to act on calcium and potassium channels? It is slow, with peak effects at 4 hours and elimination 1/2 life of 5 hours.
baclofen (b for GABA(B))
What treats spasticity in MS or spinal cord injury, but can cause hyperspacticity, rhabdomyolysis, pruritis, delirium, fever, or death after abrupt withdrawal?
baclofen
What is the exretion route of baclofen?
mostly renal, 15% liver
What drug antagonizes the NMDA receptor (decreasing glutamate) AND blocks sodium channels, treating ALS?
riluzole
What noncompetitive NMDA receptor antagonist treats Alzheimer’s?
memantine
What noncompetitive NMDA receptor antagonist treats Parkinson’s and influenza A, and should be used with levodopa for good treatment?
amantadine
What drug blocks voltage gated sodium channels and treats focal and tonic clonic seizures?
lamotrigine
What drug antagonizes the NMDA receptor (decreasing glutamate) AND blocks sodium channels, treating refractory epilepsy (focal and tonic-clonic), but can lead to aplastic anemia and hepatic failure?
felbamate
