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BM324 > Block D > Flashcards

Block D Flashcards

1
Q

what is GABA

A

amino acid that is the main inhibitory transmitter in the brain

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2
Q

what is GABA synthesised from

A

glutamate by (GAD)

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3
Q

where is GAD found

A

only in GABA-synthesising neurons in the brain

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4
Q

where is GABA found

A

exclusively in brain tissue

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5
Q

GABA metabolism steps

A

synthesis, synaptic removal, catabolism

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6
Q

GABA synthesis

A

glutamte to GABA by GAD in nerve terminals

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7
Q

GABA synaptic removal

A

GAT terminates action, sodium ion symporter (Na down GABA up)

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8
Q

GABA catabolism

A

within neuronal and non-neuronal tissue (mitochondria)
GABA to succinate by GABA-T

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9
Q

What is binding of GABA to the brain like

A

saturable and specific

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10
Q

GABA binding sites

A

GABA receptors
-binding is not sodium dependent
GABA uptake sites
-binding is sodium dependent
-neuronal and non-neuronal
-greatly outnumber GABA receptor sites

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11
Q

what are the two subtypes of GABA receptors

A

GABAa
-bicuculine sensitive
-baclofen insensitive

GABAb
-bicuculine insensitive
-baclofen sensitive

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12
Q

what type of receptors are GABAa

A

inotropic

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13
Q

what type of receptors are GABAb

A

metabotropic

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14
Q

structure of the GABAa receptor complex

A

-ligand gated chloride ion channel

-subunits are standard 4TM structure

-pentameric (5 subunits)

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15
Q

what are the GABAa receptor subunits

A

isoforms

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16
Q

GABA binding on GABAa binding sites

A

-two interfaces between alpha and beta subunits

-must bind GABA at both interfaces for activation

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17
Q

Benzodiazepine binding on GABAa binding sites

A

interfaces between alpha and gamma subunits

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18
Q

GABAa-rho receptors

A

-once known as GABAc

-similar structure to GABAa but a different pharmacology

-found in retinal bipolar cells

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19
Q

what kind of channel is GABAa-rho receptor

A

five subunit ligand-gated ion channel, composed solely of the three rho subunit varieties

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20
Q

what are GABAa-rho insensitive and sensitive to

A

insensitive
-bicucline, barbiturates, benzodiazepines, baclofen

sensitive
-CACA (agonoist), TPMPA (antagonist), picrotoxin (antagonist)

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21
Q

what kind of receptor is GABAb

A

metabotropic

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22
Q

what kind of dimer receptor is GABAb

A

hetrodimer of two 7TM receptors
-GABAb1 and GABAb2
-only b1 binds GABA to N-terminal

VFT region
-B2 binds postive allosteric modulators

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23
Q

what does GABAb couple to

A

Gi/Go

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24
Q

what is GABA in the CNS

A

inhibitory neurotransmitter, suppresses neuronal activation.

-presynaptic inhibition (axo-axonal inhibition)

-postsynaptic inhibition (recurrent inhibition)

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25
Q

what does GABA do in the spinal cord

A

reduces transmitter release from terminals of primary afferent fibres

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26
Q

why is GABA pharmacologically distinct from glycine

A

-bicuculline and picrotoxin block GABA effects

-strychnine blocks glycine effects

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27
Q

what kind of neurotransmitter is GABA in the CNS

A

inhibitory so surpasses neuronal activation

presynaptic inhibition
-axo-axonal inhibition

postsynaptic inhibition
-recurrent inhibition

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28
Q

GABA Presynaptic Inhibition

A

-reduces transmitter release from terminals of primary afferent fibres

-pharmacologically distinct from glycine

–>bicuclline and picrotoxin block GABA effects

–>styrchnine blocks glycine effects

-involves axo-axonal synaptic connections

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29
Q

axo-axonal synapses- presynaptic inhibition

A

-primary afferent fibre

-GABA neuron mediating presynaptic inhibition

-reduced release of neurotransmitter from terminal of primary afferent fibre

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30
Q

postsynaptic inhibition

A

-most GABA effects in brain

-increased chloride flux postsynpactically

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31
Q

examples of postsynaptic inhibition pathways

A

striatal (caudate putamen) -> substantia nigra

-inhibit firing of DA neurons
-direct and indirect (interneuron) effect

hippocampal and cerebral pyramidal cells

-external and recurrent inhibition

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32
Q

physiological roles of GABAb receptors

A

effects

-presynaptic decreased calcium ion fluxes
-postsynaptic increases potassium fluxes

implicated as target for management of

-pain, absence epilepsy, cocaine addition, asthma

33
Q

benzodiazepine chemical structure

A

7 membered (2N) ring fused to an aromatic ring

4 main substituent groups

34
Q

benzodiazepine mechanism of action

A

enhance presynaptic inhibition in spinal cord
-blocked by bicuculine

decreasing GABA prevents effects of BDZs
-effect requires normal levels of GABA

35
Q

benzodiazepine binding

A

-BZD clinical efficacy correlates to binding affinity

-GABA does not displace BZDs

-BZDs do not displace GABA

36
Q

location of BZD binding sites

A

-correlates to presence of GAD

-localised at GABAergic synapse

37
Q

BZD binding site

A

a specific binding site on the alpha subunit of the GABAa receptor complex

-modulates the binding of GABA to its site

-modulates the opening of the chloride ion channel

38
Q

what do classical BZDs acts as at the BZD site

A

postive allosteric modulators

-located at the interface of the alpha and gamma subunits

-enhance the inhibitory effects of GABA

39
Q

do BZDs act as agonists

A

no, their binding evokes no response

40
Q

what does BZDs enhancing the ability of activated GABA receptors to open mean

A

-increased frequency of opening

-no change in channel conductance

-no change in mean duration of opening

41
Q

interaction of GABA and BZD

A

GABA facilitates BZD binding to its binding site on the receptor

BZDs facilitate GABA binding to its binding site on the receptor

42
Q

what does the reciprocal relations between GABA and BZD result in

A

GABA shift

43
Q

what happens to the dose-response curve if BZDs are absence

A

the curve is further rightwards

44
Q

agonist has

A

affinity and positive efficacy (e=1)

45
Q

inverse agonist has

A

affinity and negative efficacy (e=-1)

46
Q

antagonist has

A

affinity and no efficacy (e=0)

47
Q

partial agonist has

A

affinity and low positive efficacy (0<e<1)

48
Q

what are endozepines

A

endogenous compounds with BZD like effects

49
Q

diazepam binding inhibitor

A
  • acyl-CoA-binding protein (10 kDa)
  • binds medium- and long-chain acyl-CoA esters
  • acts as an intracellular carrier of acyl-CoA esters
  • displaces BZD and Z-drugs from GABAA complex
50
Q

oleamide

A
  • derived from the fatty acid oleic acid
  • accumulate in thecerebrospinal fluidduringsleep deprivation
  • induces sleep in animals
  • interacts with multipleneurotransmittersystems (including cannabinoid and BDZ)
51
Q

BZD receptor “agonists”

A

-positive allosteric modulators
-Enhance GABA-mediate inhibitory effects
->increase GABA affinity for its binding site
-> increase GABA-mediated ion channel opening frequency
-Behavioural effects
-> anxiolytic, anticonvulsant
-Examples
-> diazepam, clonazepam

52
Q

Z-drugs

A

-Nonbenzodiazepine agonists of benzodiazepine receptor
-> chemically unrelated to BZD

-Zolpidem, zopiclone, zaleplon, and eszopiclone

-Clinical properties and therapeutic uses similar to BZD

53
Q

what do all Z-drugs lack

A

characteristic 7 membered ring

54
Q

BZD receptor “inverse agonists”

A

-negative allosteric modulators
-reduce GABA-mediate inhibitory effects
->decrease GABA affinity for binding site
->decrease GABA-mediated ion channel opening frequency
-reversed behavioural effects to BZDS
->anxiogenic, proconvulsant, panic attacks
-examples
->Beta-carbolines, FG-7142 (beta-carboline derivative

55
Q

BZD receptor antagonists

A

Ro-15-1788
- imidazobenzodiazepine derivative
- flumazenil *

Blocks binding
- of agonists (e.g. benzodiazepines)
- of inverse agonists (e.g. β-carbolines)

Blocks behavioural effects
- of agonists (e.g. benzodiazepines) – >can be used to treat BZD overdose
- of inverse agonists (e.g. β-carbolines)

No intrinsic behavioural effects

56
Q

BZD receptor “partial agonists”

A

Low efficacy
- cannot produce maximum response

Occupy a large proportion of receptors
- reduce response of full agonist

Partial BZD agonists
- restricted behavioural profile
- good anxiolytic effect (requires low receptor occupancy)
- poor sedative effect (requires high receptor occupancy)
- e.g. bretazenil and abecarnil

57
Q

what affect to BZDs have on CNS

A

CNS depressants
-enhance GABAs actions leading to depressants

58
Q

unwanted CNS effects of BZD-R agonists

A

Excessive CNS depression
- drowsiness, confusion, memory problems

Paradoxical CNS effects
- increased anxiety, aggressive behaviour
- more common in children, elderly and with shorter acting drugs

Habituation (dependence)
- associated with an unpleasant withdrawal syndrome

Tolerance
- loss of clinical effect on repeated administration
- greatest for hypnosis, less for anxiolysis and anticonvulsion

59
Q

therapeutic uses of BZD-R agonists

A

To treat epilepsy
- bursts of electrical activity in the CNS causing seizures or fits
- BZD strengthen inhibitory inputs, increasing seizure threshold

To treat muscle spasm
- caused by injury, inflammation or nerve disorders
- due to inhibitory action of BZDs in spinal cord

To reduce anxiety
- due to inhibitory action of BZDs in limbic system

To sedate restless patients and promote sleep

To induce surgical anaesthesia
- intravenous administration of short-acting compound

60
Q

BZD metabolism

A

Metabolised in liver
- by CYP3A4 and/or CYP2C19
- but not inducers of liver enzymes

Many primary metabolites are also BZD agonists
- needs to be factored into duration of drug effect

Many undergo glucuronidation

Excreted primarily via the kidneys
- and also in faeces

Very wide range of plasma half-lives
- from 1 hour to 5 days

61
Q

Half-life influences clinical use of BZD

A

Long half-life (30 – 60 hours) - used as anticonvulsants

Intermediate half-life (10 – 20 hours) - used as anxiolytics

Short half-life (under 10 hours) - used as hypnotics, minimises daytime sedation (hangover effect)
- shorter for problems getting to sleep
- longer for problems staying asleep

Very short half-life (1 – 3 hours)
- used as IV anaesthetics

62
Q

midazolam

A

half life= 2 hours
clinical use= intravenous anaesthetic

63
Q

flunitrazepam

A

half-life= 20-30 hours
clinical use= anxiolytic

64
Q

triazolam

A

half-life= 3-4 hours
clinical use=hypnotic

65
Q

clonazepam

A

half-life= 20-60 hours
clinical use= anticonvulsant

66
Q

flumazenil

A

Therapeutically only the BZD antagonists, i.e., flumazenil are used (in addition to agonists)

Pure antagonist of BZD and Z-drugs

Short half-life (approximately 1 hour)
- given intravenously, and often repeatedly to outlast BZD

Used in intensive care
- diagnosis of coma of unknown origin (to reveal BZD poisoning)
- treatment of BZD poisoning
Used in anaesthesia
- reversal of anaesthesia produced by a BZD
- reversal of sedation induced by a BZD used for short interventions

Used in treatment of hepatic encephalopathy
- where abnormal endogenous compounds are acting as BZD agonists

67
Q

Z-drugs versus BXD

A

Z-drugs are largely used as hypnotics

Considered more effective than BZD
- short half-life of z-drugs minimises hangover effect

Considered safer than BZD
- particularly in elderly
- but similar side-effect profile

Produce less tolerance

Produce less habituation
- reduced withdrawal problems

68
Q

where is glutamate widely distributed throughout

A

CNS

69
Q

what kind of neurotransmitter is Glutamate

A

excitatory

70
Q

metabotropic receptor structure

A

Dimeric G-protein coupled receptor
- each subunits has seven membrane-spanning region
- similar structure to muscarinic and adrenoceptors receptors

Eight identified subunit variants
- identified by molecular biology (gene sequencing)
- mGlu1 – mGlu8

Functional receptors are homodimers
- two of the same subunits
- form three physiologically and pharmacologically distinct groups

71
Q

metabotropic receptor grouping

A

Group 1
- mGlu1 and mGlu5
Group 2
- mGlu2 and mGlu3
Group 3
- mGlu4, mGlu6, mGlu7 and Glu8

72
Q

Group 1

A

coupling= Gq/11
effector mechanism= increase PLC
second messenger= increase IP3/DAG

73
Q

Group 2

A

coupling= Gi/o
effector mechamism= decrease AC
second messenger= decrease cAMP

74
Q

Group 3

A

coupling= Gi/o
effector mechanism= decrease AC
second messenger= decrease cAMP

75
Q

group 1 cellular response

A
  • located mainly on postsynaptic membranes
  • activation increases Na+ and K + conductance’s (excitation)
  • activation increases inhibitory postsynaptic potentials (inhibition)
  • activation leads to modulation of voltage-dependent Ca2+ channels
76
Q

Group 2 and 3 cellular response

A
  • located mainly on presynaptic membranes
  • activation has no direct effect on postsynaptic potentials
  • activation leads to increased presynaptic inhibition
  • activation leads to reduced activity of postsynaptic potentials (both excitatory and inhibitory)
77
Q

metabotropic receptor functional roles

A

Modulation of NMDA receptor function
- group I increase NMDA receptor activity
- groups II/III decrease NMDA receptor activity (protect from excitotoxicity)

Synaptic plasticity
- participate in long-term potentiation and long-term depression (removed from synaptic membrane in response to agonist binding)

Control of hypothalamic-pituitary-adrenal axis
- regulation of cortisol levels and stress responses

Putative role in disease
- expression of mGlu1 may be involved in development of certain cancers
- evidence for mGlu2/3 agonists (eglumegad) in treatment of schizophrenia
- activation of mGlu4 receptors could treat Parkinson’s disease

78
Q

inotropic glutamate receptors

A

NMDA, AMPA, kainate, delta
- integral receptor/cation channels
- each receptor composed of four subunits

Multiple subunits for each major class of receptor
- NMDA: GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A, GluN3B- AMPA: GluA1, GluA2, Glu3, GluA4
- kainate: GluK1, GluK2, GluK3, GluK4, GluK5
- delta: GluD1, GluD2

BM324 (2 decks)

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