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Pharmacology > GABAergic and Glutamatergic Neurotransmission, GABAergic and Glutamatergic Drugs > Flashcards

GABAergic and Glutamatergic Neurotransmission, GABAergic and Glutamatergic Drugs Flashcards

1
Q

Distribution of GABA throughout the brain

A

Widely and uniformly distributed throughout the brain

in contrast to most other neurotransmitters which have a localised, discrete distribution (e.g. ACh, NA, dopamine and serotonin)

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2
Q

Synthesis, storage, release, termination and metabolism of GABA

A
  1. Glutamate is taken into neuron via carrier mediated transport
  2. Glutamate is decarboxylated to GABA by glutamic acid decarboxylase
  3. GABA is actively packaged into vesicles by a specific transporter
  4. Release is via classical Ca2+ mediated exocytosis
  5. Termination is via uptake by a GABA transporter
  6. Degradation is via GABA transaminase
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3
Q

2 types of GABA receptors

A

GABAA

GABAB

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4
Q

GABAA

  1. MOA
  2. Subunit composition
A
  1. Ligand gated ion channel
  2. Pentamer - α, β, γ subunits (3-6 of each subunit)
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5
Q

GABAB

  1. MOA
  2. Subunit composition
A
  1. Gi protein via AC and decreased cAMP
  2. Dimer
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6
Q

what is the GABAA receptor permeable to

A

permeable to Cl-

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7
Q

what are the receptor targets of GABAA receptor

A

GABA site - agonists and antagonists

benzodiazepine site - enhance actions of GABA

barbiturate site - enhance actions of GABA

neurosteroid site - enhance actions of GABA

picrotoxin site - blocks Cl- channel (hyperpolarisation so more difficult for cell to be activated)

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8
Q

drugs that enhance actions of GABA

A

benzodiazepines

barbiturates

neurosteroids

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9
Q

what drug blocks Cl- channel on GABAA receptor

A

picrotoxin

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10
Q

what sort of transmitter is GABA

A

INHIBITORY

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11
Q

GABAA

  1. cellular location
  2. response
  3. MOA
A
  1. postsynaptic
  2. fast postsynaptic inhibition
  3. channel is selectively permeable to Cl- - increasing Cl- permeability hyperpolarises cell, thereby reducing its excitability
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12
Q

GABAB

  1. cellular location
  2. response
  3. MOA
A
  1. pre and post synaptic
  2. pre and post synaptic inhibition
  3. inhibits VG Ca2+ channels (inhibits transmitter release) - opens K+ channels (reduces postsynaptic excitability)
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13
Q

general functions of GABA

A

general CNS depression/inhibition

regulates/modulates the activity of other NT systems

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14
Q

where is glutamate found in the brain

A

widely and uniformly distributed - in contrast to most other NTs

(opposite of GABA)

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15
Q

Synthesis, storage, release, termination, metabolism of glutamate

A
  1. glutamine is taken into neuron via carrier mediated transport
  2. glutamine is converted to glutamate by glutaminase
  3. glutamate is actively packaged into vesicles by a specific transporter
  4. release is via classical Ca2+ mediated exocytosis
  5. termination is via uptake by a glutamate transporter
  6. degradation is via glutamine synthase
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16
Q

what are the main glutamate receptor subtypes

A

NMDA

AMPA

Kainate

Metabotropic

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17
Q

NMDA

  1. MOA
  2. subunit composition
A
  1. ligand gated ion channel
  2. pentamer - NR1 and NR2 subunits
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18
Q

AMPA

  1. MOA
  2. subunit composition
A
  1. ligand gated ion channel
  2. pentamer - GluR1-4 subunits
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19
Q

Kainate

  1. MOA
  2. subunit composition
A
  1. ligand gated ion channel
  2. pentamer - GluR5-7 and KA1-2 subunits
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20
Q

metabotropic

  1. MOA
  2. subunit composition
A
  1. Gq protein coupled
  2. PLC and increased IP3/DAG/Ca2+
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21
Q

NMDA

A

N-methyl D-aspartate

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22
Q

what is the NMDA receptor permeable to

A

Na+

Ca2+

K+

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23
Q

what are the facilitatory sites on the NMDA receptor

A

glutamate - agonists/antagonists

glycine - required for channel opening

polyamine side - polyamines facilitate channel opening

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24
Q

site on NMDA receptor required for channel opening

A

glycine

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25
Q

site on NMDA receptor that facilitates channel opening

A

polyamine side

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26
Q

what are the inhibitory sites on the NMDA receptor

A

Mg2+ - channel is normally blocked by Mg2+ when the cell is normally polarised but is overcome when the cell is depolarised

Zn2+ - binding of Zn2+ inhibits receptor opening

channel blocking drug site - certain drugs, e.g. PCP, selectively block the channel

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27
Q

glutamate = main ________ NT in the brain

A

excitatory

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28
Q

NMDA

  1. cellular location
  2. response
A
  1. postsynaptic
  2. slow EPSP

NB - synaptic plasticity and excitotoxicity

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29
Q

AMPA

  1. cellular location
  2. response
A
  1. postsynaptic
  2. fast EPSP
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30
Q

Kainate

  1. cellular location
  2. response
A
  1. pre and postsynaptic
  2. fast EPSP
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31
Q

metabotropic

  1. cellular location
  2. response
A
  1. pre and post synaptic
  2. synaptic modulation
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32
Q

what are glutamatergic antagonists used to treat

A

Head injury and stroke

reduce excitotoxic brain damage following head injury and stroke

Epilepsy

some anti-epileptic drugs work by antagonising glutamate receptors, specifically AMPA subtype (e.g. perampanel)

33
Q

perampanel

A

anti-epileptic drug

antagonises glutamate receptors, specifically AMPA

34
Q

epilepsy

prevalence

what are possible causes

A

neurological disorder characterised by seizures

seizures are caused by high freq discharge of a group of neurons in the brain

usually start locally but can spread to other areas of the brain

symptoms depend on region of brain affected

affects 0.5-1% of the population

usually no recognisable cause but MAY occur after brain damage (trauma, infection, tumour) or in certain inherited neurological disorders

35
Q

how is epilepsy characterised

A

Partial seizures: simple (if patient remains conscious) OR complex (if patient loses consciousness)

generalised seizures: tonic-clonic (grand mal) OR absence (petit mal)

36
Q

tonic phase of tonic-clonic seizures (grand mal)

A

an initial strong contraction of the whole musculature

rigid extensor spasm

respiration may stop

defecation, micturition and salivation may occur

37
Q

clonic phase of tonic-clonic seizures

A

series of violent synchronous jerks

lasts 2-4 mins

patient recovers consciousness feeling ill and confused

38
Q

epileptic absence seizures

brain regions involved

frequently seen in what demographic

A

patient abruptly stops whatever he/she is doing and stares vacantly for a few seconds

patient is unaware of his/her surroundings and recovers abruptly with little after effects

absence seizures frequently occur in children

EEG pattern reflects neural oscillations between thalamus and cortex - due to T type Ca2+ channels

39
Q

what happens if there is a seizure in the reticular formation

A

lose consciousness

40
Q

what MAY cause epileptic seizures

A

enhanced excitatory AA (glutamate) transmission

reduced inhibitory AA (GABA) transmission

abnormal electrical properties of the affected cells

41
Q

what can repeated epileptic discharge cause

A

neuronal death through excitotoxic mechanisms

42
Q

Lennox-Gastaut syndrome

A

severe form of epilepsy

affects children

associated with progressive mental retardation (probably occurs as a result of neurodegeneration)

Glutamate acting on NMDA receptor - Ca2+ in - NMDA receptor keeps letting it in - damage lipids etc - progressive mental dysfunctionality

43
Q

synonym for anti-epileptic drugs

how effective are they

A

fully effective in treating seizures in 50-80% of patients

anti-convulsant drugs

44
Q

4 most important anti-epileptic drugs in use

A

phenytoin

carbamazepine

valproate

ethosuximide

45
Q

other long established anti-epileptic drugs

A

barbituates e.g. phenoarbital although it is an anaesthetic so only for extreme epileptic states

benzodiazepines e.g. diazepam, clonazepam, lorazepam

46
Q

danger associated with sodium valproate

A

causes foetal abnormalities in pregnant women

47
Q

newer anti-epileptic drugs

A

vigabatrin

gabapentin

lamotrigine

felbamate

tiagabine

topiramate

levetiracetam

zonisamide

pregabalin

retigabine

perampanel

lacosamide

stiripentol

48
Q

4 distinct mechanisms of anti-epileptic drugs

A
  1. enhancement of GABA action
  2. inhibition of VG Na+ channel function
  3. inhibition of VG Ca2+ channel function (responsible for releasing NTs)
  4. antagonism of glutamate receptors

aim = to prevent ABNORMAL discharge while leaving NORMAL discharge intact

49
Q

how do anti-epileptic drugs enhance GABAergic transmission

A

+ve allosteric modulation of GABAA receptor e.g. barbituates and benzodiazepines

inhibition of GABA transaminase e.g. vigabatrin

inhibition of GABA uptake e.g. tiagabine

50
Q

metabolism of GABA

51
Q

MOA of barbituates and benzodiazepines

A

+ve allosteric modulation of GABAA receptor

52
Q

MOA of vigabatrin

A

inhibition of GABA transaminase

53
Q

MOA of tiagabine

A

inhibition of GABA uptake

54
Q

explain MOA of benzodiazepines

A

enhance GABAergic transmission at GABAA receptor (a ligand gated ion channel receptor, permeable to Cl- and thus opening the channel hyperpolarises neuron and reduces its excitability)

benzodiazepines bind to GABAA receptor at a different site to GABA and increase the affinity of GABA for the receptor

55
Q

MOA of phenytoin, carbamazepine, valproate, lamotrigine

A

inhibit VD Na+ channel function thereby reducing neuronal membrane excitability

prevents propagation of APs

their blocking action shows the phenomenon of use dependence - they preferentially block the excitation of neurons that are firing repetitively

use dependence occurs because these anti-epileptic drugs preferentially bind to inactivated state of Na+ channel

56
Q

use dependence

A

preferentially block the excitation of neurons that are firing repetitively

57
Q

MOA of ethosuximide and valproate

A

inhibit T type VG Ca2+ channel function that underpins absence seizures

58
Q

MOA of gabapentin and pregabalin

A

bind to a subunit of P/Q-type VG Ca2+ channels thereby preventing it from trafficking to the membrane

reduces Ca2+ dependent exocytosis of synaptic vesicles

59
Q

MOA of perampanel

A

antagonises glutamate receptors, specifically the AMPA subtype

60
Q

normal fear response to threatening stimuli

A

defensive behaviour

autonomic reflexes

arousal and alertness

corticosteroid secretion

negative emotions

in anxiety states, these reactions occur in an anticipatory manner independent of external events

anxiety becomes pathological when these symptoms interfere with normal function

61
Q

generalised anxiety disorder

A

ongoing state of anxiety with no clear reason

62
Q

social anxiety disorder

A

fear of being/interacting with other people

63
Q

panic disorder

A

attacks of overwhelming fear in association with marked somatic symptoms - sweating, tachycardia, chest pains, trembling, choking

64
Q

OCD

A

compulsive ritualistic behaviour driven by irrational anxiety

65
Q

PTSD

A

anxiety triggered by insistent recall of past stressful experiences

66
Q

types of anxiolytic drugs

A

benzodiazepines

drugs used for depression

5-HT1A receptor agonists

β-adrenoceptor antagonists

drugs used for epilepsy

drugs used for schizophrenia

67
Q

anxiolytic drugs - benzodiazepines

A

diazepam - Valium

alprazolam - Xanax

68
Q

anxiolytic drugs - drugs used for depression

A

SSRIs e.g. fluoxetine (Prozac)

69
Q

anxiolytic drugs - 5-HT1A receptor agonists

70
Q

anxiolytic drugs - β-adrenoceptor antagonists

A

β blockers e.g. propranolol

especially for panic disorder to stop triggering the sympathetic drive

71
Q

anxiolytic drugs - used for epilepsy

A

gabapentin

pregabalin

72
Q

anxiolytic drugs - used for schizophrenia

A

olanzapine

risperidone

73
Q

categories of benzodiazepines

A

ultrashort duration

short duration

medium duration

long duration

74
Q

ultrashort duration benzodiazepines

A

midazolam

zolpidem (Ambien) - not strictly a benzodiazepine but similar MOA

75
Q

short duration benzodiazepines

A

lorazepam

temazepam

76
Q

medium duration benzodiazepines

A

alprazolam

nitrazepam

77
Q

long duration benzodiazepines

A

diazepam (Valium)

chlordiazepoxide

78
Q

drugs mainly used as hypnotics/sleeping pills

A

midazolam

zolpidem (Ambien)

79
Q

pharmacological effects of benzodiazepines

A

reduction of anxiety and aggression

sedation and induction of sleep

short durations - dependence can occur + rebound insomnia

reduction of muscle tone and co-ordination

relax muscle spasm e.g. slipped disc, headache as a result of increased muscle tone with anxiety

anticonvulsant effects

useful for life threatening status epilepticus (unbroken series of seizures)

anterograde amnesia

prevent formation of memories while on drug - flunitrazepam (Rohypnol = “date rape” drug)

Pharmacology (23 decks)

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