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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
site on NMDA receptor that facilitates channel opening
polyamine side
26
what are the inhibitory sites on the NMDA receptor
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
27
glutamate = main ________ NT in the brain
excitatory
28
NMDA 1. cellular location 2. response
1. postsynaptic 2. slow EPSP NB - synaptic plasticity and excitotoxicity
29
AMPA 1. cellular location 2. response
1. postsynaptic 2. fast EPSP
30
Kainate 1. cellular location 2. response
1. pre and postsynaptic 2. fast EPSP
31
metabotropic 1. cellular location 2. response
1. pre and post synaptic 2. synaptic modulation
32
what are glutamatergic antagonists used to treat
**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
perampanel
anti-epileptic drug antagonises glutamate receptors, specifically AMPA
34
epilepsy prevalence what are possible causes
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
how is epilepsy characterised
***Partial seizures:*** _simple_ (if patient remains conscious) OR _complex_ (if patient loses consciousness) ***generalised seizures:*** _tonic-clonic_ (grand mal) OR _absence_ (petit mal)
36
tonic phase of tonic-clonic seizures (grand mal)
an initial strong contraction of the whole musculature rigid extensor spasm respiration may stop defecation, micturition and salivation may occur
37
clonic phase of tonic-clonic seizures
series of violent synchronous jerks lasts 2-4 mins patient recovers consciousness feeling ill and confused
38
epileptic absence seizures brain regions involved frequently seen in what demographic
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
what happens if there is a seizure in the reticular formation
lose consciousness
40
what MAY cause epileptic seizures
enhanced excitatory AA (glutamate) transmission reduced inhibitory AA (GABA) transmission abnormal electrical properties of the affected cells
41
what can repeated epileptic discharge cause
neuronal death through excitotoxic mechanisms
42
Lennox-Gastaut syndrome
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
synonym for anti-epileptic drugs how effective are they
fully effective in treating seizures in 50-80% of patients anti-convulsant drugs
44
4 most important anti-epileptic drugs in use
phenytoin carbamazepine valproate ethosuximide
45
other long established anti-epileptic drugs
barbituates e.g. phenoarbital although it is an anaesthetic so only for extreme epileptic states benzodiazepines e.g. diazepam, clonazepam, lorazepam
46
danger associated with sodium valproate
causes foetal abnormalities in pregnant women
47
newer anti-epileptic drugs
vigabatrin gabapentin lamotrigine felbamate tiagabine topiramate levetiracetam zonisamide pregabalin retigabine perampanel lacosamide stiripentol
48
4 distinct mechanisms of anti-epileptic drugs
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
how do anti-epileptic drugs enhance GABAergic transmission
+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
metabolism of GABA
51
MOA of barbituates and benzodiazepines
+ve allosteric modulation of GABAA receptor
52
MOA of vigabatrin
inhibition of GABA transaminase
53
MOA of tiagabine
inhibition of GABA uptake
54
explain MOA of benzodiazepines
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
MOA of **phenytoin, carbamazepine, valproate,** lamotrigine
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
use dependence
preferentially block the excitation of neurons that are firing repetitively
57
MOA of ethosuximide and valproate
inhibit T type VG Ca2+ channel function that underpins absence seizures
58
MOA of gabapentin and pregabalin
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
MOA of perampanel
antagonises glutamate receptors, specifically the AMPA subtype
60
normal fear response to threatening stimuli
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
generalised anxiety disorder
ongoing state of anxiety with no clear reason
62
social anxiety disorder
fear of being/interacting with other people
63
panic disorder
attacks of overwhelming fear in association with marked somatic symptoms - sweating, tachycardia, chest pains, trembling, choking
64
OCD
compulsive ritualistic behaviour driven by irrational anxiety
65
PTSD
anxiety triggered by insistent recall of past stressful experiences
66
types of anxiolytic drugs
benzodiazepines drugs used for depression 5-HT1A receptor agonists β-adrenoceptor antagonists drugs used for epilepsy drugs used for schizophrenia
67
anxiolytic drugs - benzodiazepines
diazepam - Valium alprazolam - Xanax
68
anxiolytic drugs - drugs used for depression
SSRIs e.g. fluoxetine (Prozac)
69
anxiolytic drugs - 5-HT1A receptor agonists
busiprone
70
anxiolytic drugs - β-adrenoceptor antagonists
β blockers e.g. propranolol especially for panic disorder to stop triggering the sympathetic drive
71
anxiolytic drugs - used for epilepsy
gabapentin pregabalin
72
anxiolytic drugs - used for schizophrenia
olanzapine risperidone
73
categories of benzodiazepines
ultrashort duration short duration medium duration long duration
74
ultrashort duration benzodiazepines
midazolam zolpidem (Ambien) - not strictly a benzodiazepine but similar MOA
75
short duration benzodiazepines
lorazepam temazepam
76
medium duration benzodiazepines
alprazolam nitrazepam
77
long duration benzodiazepines
diazepam (Valium) chlordiazepoxide
78
drugs mainly used as hypnotics/sleeping pills
midazolam zolpidem (Ambien)
79
pharmacological effects of benzodiazepines
**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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