Glutamate and GABA Amino Acid Neurotransmitters, Receptors, and Drugs PT 2 Flashcards
Benzodiazepine drugs types
- allosteric agonists
- allosteric antagonists
allosteric agonists used clinically names and fxs
they are minor tranquilizers or anxiolytics
- chlordiazepoxide (Librium)
- Diazepam (Valium)
- flurazepam (Dalmane)
- Oxazepam
- Lorazepam
- Prazepam
Competitive antagonists at benzodiazepine allosteric site drug class and name
- competitive antagonists
- flumazenil
Mechanism of action benzodiazepine
- enhance inhibitory actions GABA
- Interact with specific site on GABAa receptor-chloride channel complex associated with receptor containing gama2 subunit
Benzodiazepines are both
- anxiolytic
- sedating
allosteric agonists benzodiazepines require
the presence of gama2 subunit
Benzodiazepine agonists prefer what subunits be present or not present
- alpha 1,2,3,5 present
- alpha 4,6
Benzodiazepine antagonists prefer
- alpha 1 subunits to alpha 2 and alpha 3 and they do not interact with alpha 5
- this means they are not complete reversal agents
GABA bound with vs without diazepam effect
GABA bound opens channels, GABA and Diazepam bound -> channels open longer
Benzodiazepine drugs toxicity
- fairly safe no remarkable acute toxicity
- withdraw following chronic uses can -> seizures
- use benzodiazepines with barbiturates or alcohol can -> death
clinical uses benzodiazepine drugs
- anxiolytic (anti-anxiety) (used in combo with other CNS deprassants in pre-anesthetic protocols)
- anti-convulsant at v high doses give IV can control status epileptics
- muscle relaxant- increases inhibition in spinal cord
Excitatory animo acid neurotransmitters
-mainly L-glutamate
May also include
- L-asparate
- L-homocystetic acid
Receptor class for excititaroy amino acid neurotransmitters name
glutamate receptors or excitatory amino acid receptors
glutamate receptors and CNS
- nearly all CNS neurons have excitatory glutamate receptors
- nearly 1/3 CNS neurons= glutamatergic
Glutamate receptors and excitatory amino acid receptors subclasses
- provide some specificity and different patterns of regional distribution of different glutamate receptor subtypes occur in brain and spinal cord
NMDA-type glutamate receptors
- pain pathways
- hippocampus (role in learning and memory)
synthesis of L-glutamate
can be:
- by deamination L-glutamine
- from a-ketoglutarate
synthesis L-aspartate
can be:
- by transmission oxalacetate
- by deacetylation of N-acetylaspartate
degradation L-glutamate
pathway unknown
synaptic action L-glutamte stopped how?
- mainly by high affinity uptake mechanisms
- diffusion also plays a role
- non-specific processes
what cells have glutamate uptake systems
neuronal and glial cells
Glutaminergic synapses compartments
- tripartite, have 3 components
- presynaptic terminal
- postsynaptic button
- enveloping astrocyte
Astrocytes fx
- pt of glutaminergic synapse
- respond to glutamate and transmit info throughout network of neurons that contact astrocyte
Inotropic Glutamate receptors (excitatory amino acid receptors) receptor subtypes
- named for agonists
- N-methyl-D-aspartate (NMDA)
- AMPA
- kainate
Ionotropic glumate receptors permeable to
Na+ and K+ ions, NMDA to Ca2+
AMPA receptors important for
generating fast excitatory postsynaptic potentials (EPSPs) in CNS
important binding sites on NMDA receptors
- glutamate receptor site where neurotransmitter binds
- Mg2+ site inside pore
- PCP site
Mg2+ site at normal resting potentials
Mg2+ ions block flow other ions through pore
PCP site
binds dissociative anesthetic drugs (ketamine and tiletamine)
Uncompetitive antagonists
- dissociate anesthetic drugs
- use-dependent antagonists of NMDA receptor-channels (aka NMDA channel blockers)
How do uncompetitive antagonists work
- they’re use depdnet so active glutamate synapses more likely to be inhibited by dissociated anesthetics than less active ones
details: - drug enters binding site inside channel, channel closes drug trapped, drug can’t leave channel until its re-opened by release neurotransmitter again
Dissociate anesthetics characterized by
loss of awareness accompanied by body surface analgesia
examples drugs used in dissociative anesthesia
- ketamine
- tiletamine
- phencyclidine (PCP)
Ketamine
- dissociative anesthetic
- preanesthetic drug
ketamine as a preanesthetic drug
- b/c it causes dysphoria use with nonadrenergic alpha-2 agonist or benzodiazepines which provide sedation or tranquilization
noradrenergic alpha2 agonist examples
detomidine, medetomidine
benzodiazepine example
diazepam
Tiletamine
- dissociate anesthetic drug
- can use in combo with benzodiazepine or noradrenergic alpha 2 agonist
Phencyclidine
- dissociate anesthetic drug
- PCP
- UK primary anesthetic US illegal street drug
disadvantages of dissociative anesthetics
- strong dysphoric rxns as drug wears off
- uncompetitive agonist so no possibility of reversal agent (bc any drug competing for same sit will have same effect)
- do not give as sole agent for anesthesia recovery difficult if not given with sedative or anxiolytic drug
advantages of dissociative anesthetics
- analgesia
- cause amnesia
- may protect brain from exotic cell death during hypoxic episodes
- maintain or increase cardiac output
why analgesia with dissociative anesthetics
- blockade of NMDA channels (which are pt pain pathway at glutamatergic synapses)
excitotoxic cell death with excitatory amino acid neurotransmitter
continuous glutamate exposure depolarizes neurons for prolonged periods b/c NMDA channels highly permeable to Ca2+; overly active NMDA channels cause sustained increase in intracellular Ca2+ concentration activating Ca2+ dependent proteases (caspases) -> mitochondrial damage and subsequently to neuronal death
excitatory amino acid receptors aka
glutamate receptors
Examples excitotoxicity
- Hypoxic/ Ischemic reprofusion damage
2. In untreated seizure disorders
excitotoxicity hypoxic/ischemic reperfusion damage
- cerebral ischemia
2. glutamate released from injured and dying neurons goes into extracellular space and bathes nearby neurons
excitotoxicity in untreated seizure disorder
excessive glutametergic stimulation kills neurons
