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43 Cards in this Set

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what are the three main subtypes of glutamate-gated ion channels?
1. AMPA
2. NMDA
3. Kainate
AMPA receptors
found throughout CNS
- NA influx (excitatory)
Kainate receptors
found throughout CNS
- NA influx and K efflux
- may be used to code for pain intensity
NMDA
- hippocampus, cerebral cortex and spinal cord
- receptor opening requires simultaneous binding of glutamate and glycine
- requires depolarization to get rid of Mg block even after NT binding
- K, Na, and Ca influx
memantine
non competitive NMDA receptor antagonist that does not cause the side effects associated with competitive receptor antagonists
- 'use dependent'!
give the mechanism for apoxic injury
mit are not able to maintain ionic gradients, and the Na couple glutamate-Na coupled transporters don't work.
- increased glutamate causes increased opening of NMDA channels
- increase Ca, Na, and K influx
- increased Ca actiaves many Ca dependent degredation enzymes (DNAse, proteases, phosphatases, phospholipases)
memantine
noncompetitive NMDA receptoror antagonist that has few side effects.
- is use dependent
- allows low levesl of receptor activation during physiologic stimulation but prevents higher levle sof activation
how do AMPA receptor antagonists help against ischemic injury?
- don't let Ca entry through AMPA receptors
- added effect of preventing depolarization --> reduced activation of NMDA receptors and voltage-activated Ca channels
hyperalgesia
extreme sensitivity to pain
- modulated by NMDA receptors
Lamotrigine
used to treat refractory complex partial seizures
- stabilizes the inactivated state of the voltage-gated Na channel --> reduces membrane excitability
pathogenesis of ALS
defect in glutamate transporters in the spinal cord and motor cortex --> increased [glutamate] --> motor neuron death via excitotoxicity
riluzole
voltage-gated Na channel blocker for treatment of ALS --> decrease glutamate release
- cerebroprotective, antiepileptic, and analgesic effects
CNQX
AMPA receptor antagonist for treatment of ALS
amantadine
noncomeptitive blocker of NMDA receptor channels
- used to treat Parkinson's disease
synthesis of GABA
depends on the glutamic acide decarboxylase (GAD)
-decarboxylation of glutamate to GABA in nerve terminals
cofactor for GAD
pyridoxal phosphate (Vitamin B6)
Difference between GABA_A and GABA_B
ionotropic GABA_A: fast IPSPs
metabotropic GABA_B: slow IPSPs
GABA_A
ligand gated Ca channel that opens immediately after GABA binding
GABA_B
7 membrane G protein receptor. Opens K channels
- expressed at lower elvels than GABA A
- found primarily in spinal cord
baclofen
GABA_B receptor agonist
gabaculine
inhibits GABA-T: enzyme responsible for degredation of GABA ot succinic semialdehyde
- anticonvulsive effects
Allylglycine
inhibits glutamic acid decarboxylase --> lowered GABA levels --> convulsant
Isoniazid
inhibits pyridoxal kinase (antivitamin B6) --> lowered GABA levels --> convulsant at high doses
Tetanus Toxin
inhibit GABA and glycine release --> convulsant
Muscimol
GABA_! receptor agonist --> mimics psychosis
Baclofen
GABA_B receptor agonist --> muscle relaxant
Bicucullin
competitve receptor antagonist --> convulsant
Picrotoxin
noncompetitive GABA antagonist --> convulsant
Benzodiazepines
potentiate GABA binding --> anticonvulsant, anxiolytic
Barbituates
increase GABA efficacy, weak agonist --> anticonvulsant, anesthetic
where do sedative/anxiolytic and hypnotic drugs act?
at the GABA_A receptor. The receptor also has a
1. barbiturate binding site (that also binds IV general anesthetic and CNS depressants)
2. a bezodiazepine binding site
3. a steroid binding site
how do benzodiazepines and barbiturates act?
primarily by alering the interaction between GABA_A receptor and GABA.
barbiturates
increased GABAergic trasnmission at the brainstem: suppression of the reticular activating system --> sedation, amnesia, and loss of consciousness
increased GABAergic transmission at the motor neurons in the spinal cord --> releases muscles and suppresses reflexes
- decrease activation of AMPA receptor by glutamate
which are used more in clinical settings: benzodiazepines or barbiturates?
Why?
benzodiazepine:
- cause less tolerance
- have fewer withdrawl symptoms
- have less impact on drug-metabolizing enzymes
- higher selectivity and less toxic potential
why are barbiturates dangerous?
synergize with GABA at GABA_A receptors
- independently activate GABA_A channels!!
what are barbiturates good for?
anti-epileptics
phenobarbital hyperpolarize the neuron --> decrease neuronal excitability --> raise seizure threshold.
relationship between barbiturates and P450 oxidases
P450 inducer
how do you treat barbiturate overdose?
- respiratory and cardiovascular support
- activated charcoal for drug chelation
- alkalinization of urine to increase barbiturate clearance
why are benzodiazepines safter than barbiturates?
benzos increase the frequnecy of channel opening instead of increaseing the duration of Cl channel opening (barbit).
- benzos increase the likelihood of opening by increasing the binding affinity between GABA and the GABA_A receptor
- benzos have no intrinsic agonist activity
flumazenil
used to treat benzodiazepine overdose
- competitive blocker of benzo bindng to GABA_A receptor
diazepam and aprazolam
benzos used for:
- chronic severe anxiety
- anxiety that accompanies depressiona nd schizophrenia
mechanism of benzodiazepine tolerance
decreased expressin of GABA_A receptors
ethanol molecular targets
believed to have some effect on GABA_A as well.
- inhibition of NMDA receptor activation (endogenous ligand: glutamate)