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anxiolytics Flashcards

1
Q

barbiturates (derivatives of barbital)

A

amobarbital
pentobarbital
thiopental
phenobarbital

-note al ending (also see -one ending)

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2
Q

historical uses of barbiturates

A

Anxiolytics
Anticonvulsants
Sedatives/hypnotics
Anaesthetics

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3
Q

barbiturates and overdose

A

very dangerous in overdose

respiratory depression

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4
Q

when are barbiturates used as anxiolytics and anticonvulsants

A

in extreme cases

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5
Q

when are barbiturates used as anaesthetics?

A

for induction or very short procedures

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6
Q

mechanism of action of barbiturates

A

Mainly positive allosteric modulators of GABAA receptor: prolong channel opening time (make GABA work better)

At higher concentrations can bypass GABA and directly activate the receptor

may also inhibit AMPA receptors, P/Q type voltage sensitive channels (inhibits NT release)

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7
Q

why are barbiturates so dangerous in overdose?

A

because they can directly activate GABA receptors

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8
Q

general mechanism of action or barbiturates

A

boost inhibitory transmission

can decrease excitatory transmission

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9
Q

how do barbiturates act on GABA A receptors?

A

site of action of GABA A receptor is fairly poorly characterised

think they have a binding site in the beta subunit, so they are acting within the membrane domain

some have suggested that the binding site might extend into the neighbouring alpha subunit as well

these are drugs that would need to enter the lipid bilayer to access their binding site

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10
Q

uses of thiopental

A

general anaesthesia

occasionally used in status epilepticus when a seizure has not responded to benzodiazepines or anticonvulsants (also pentobarbital)

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11
Q

current uses of barbiturates

A

general anaesthesia

status epilepticus

used to induce comas at higher dioses in medical veterinary euthanasia

used in lethal injections as a dorm of capital punishment

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12
Q

lethal injection common cocktail

A

sodium thiopental
pancuronium bromide
potassium chloride

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13
Q

purpose of sodium thiopental in lethal injection cocktail

A

induce loss of consciousness and repress respiratory drive

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14
Q

replacement drugs for lethal injection used since 2011

A

using pentobarbital or a benzodiazepine/ opioid mixture as a replacement

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15
Q

why did benzodiazepines replace barbiturates?

A

because they are safer in overdose

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16
Q

what was the first barbiturate synthesised?

A

chlordiazepoxide

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17
Q

effects of benzodiazepines

A

anxiolytic

sedative

muscle relaxant

amnesic

anticonvulsant

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18
Q

why are barbiturates use sparingly

A

used at low dose and short term because tolerance builds up quickly

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19
Q

where is the benzodiazepine binding site on GABA A?

A

on the interfaces of alpha 1 and gamma 2

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20
Q

benzodiazepine agonists

A

flunitrazepam
diazepam
temazepam
nitrazepam

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21
Q

mechanism of benzodiazepine agonists

A

increase GABA a receptor channel opening frequency

can also increase affinity for GABA binding sites

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22
Q

benzodiazepine

A

flumazenil
pharmacologically fairly inactive
applied alone has little effect on GABA A

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23
Q

what is flumazenil used for?

A

to block potentiation by flunitrazepam

therefore used to reverse benzodiazepine sedation (overdose)

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24
Q

why is it quite difficult to manage flumazenil?

A

it isn’t a perfect antagonist

it can show a bit of inverse agonist activity and at other doses can show agonist activity

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25
benzodiazepine inverse agonists
B carbolines (DMCM) proconvulsant anxiogenic decrease channel opening frequency
26
what can block the action of B carbolines
by flumazenil
27
SAM meaning
silent allosteric modulator
28
Two distinct CNS populations defined by binding studies
CL218-872: High affinity for Cl: Type I benzodiazepine binding sites Low affinity for Cl: Type II differ in regional distribution receptor heterogeneity?
29
benzodiazepine and alpha 1 subunit
type 1 BDZ binding site - binds classic BDZs
30
benzodiazepine and alpha 2, 3, 5 subunit
type II BDZ binding site - binds classic BDZs
31
benzodiazepine and alpha 4, 6 subunit
high affinity for Ro 15-4513, but not for classic BDZs
32
Ro compound
synthesised by Roche discovered it was an alcohol antagonist considered marketing it as an alcohol antagonist and antidote, but decided that the ethical issues were too great
33
what does pharmacology of benzodiazepine binding site depend on?
the alpha subunit at the alpha gamma interface of a GABA A receptor
34
use of BDZ when first introduces
first line treatments for anxiety and sleep disorders also frequently used as anticonvulsants
35
what are most BDZ used for today?
anxiety or sleep disorders (or both) Some are used as sedatives for minor surgical procedures (especially midazolam), to aid with alcohol withdrawal (chlordiazepoxide) or epilepsy (clobazam, clonazepam) Diazepam is also used for muscle spasms
36
use of midazolam
sedative for minor surgical procedure
37
use of chlordiazepoxide
to aid with alcohol withdrawal
38
use of clobazam and clonazepam
treatment of epilepsy
39
use of diazepam
treat muscle spasms
40
what are the z deugs
zaleplon zopiclone zolpidem
41
what are z drugs used for
primarily for the treatment of sleep disorders -hypnotics or sleeping tablets
42
features of z drugs
tolerance and dependence can develop (though more slowly that drugs like diazepam) Normally only prescribes in low doses for a short period of time e.g., 14-28 days They have short plasma half lives -most useful for people who have trouble falling asleep -zapelon: 1hr, zolpidem: 2.5hrs, zopiclone: up to 6 hrs Their rapid elimination can help avoid ‘hangover’ effects that are seen with older drugs like diazepam (half life 48 hrs)
43
oppositional tolerance model with reference to benzodiazepines
GABAergic transmission is potentiated so the reaction of the brain is to down-regulate GABAergic transmission causes tolerance to the drug to develop and results in withdrawal symptoms if the person using the drug abruptly stops taking it
44
tolerance and dependence with BDZ
Can develop rapidly and this is one of the reasons that they are recommended only for short term use (28 days maximum)
45
withdrawal effects BDZ
Withdrawal effects can develop rapidly, especially with drugs with a short half life such as alprazolam (Xanax) said to be harder than coming of heroin and can involve a wide range of unpleasant side effects: -hallucinations, increased anxiety, insomnia through to photophobia (abnormal sensitivity to light)
46
why do we want to develop anxioselective BDZ ligands?
Fundamental premise: we have different types of GABA A receptors involved with anxiolytic effects compared with those involved with the sedative effects of BDZ agonists different subunit compositions in these receptors Aim to develop BDZ that produces anxiolytic effects, while avoiding sedative effects. Or visa versa
47
drugs in first wave of studies
bretazenil alpiden and ocinaplon
48
bretazenil
Animal studies suggested anxiolysis but little sedation. Human phase I trials: profound sedation and stronger interaction with ethanol than diazepam Points to a difference in GABA A receptors in humans and animals
49
interaction between bretazenil ethanol
found to be stronger than that of ethanol and diazepam
50
alpidem, ocinaplon
Worked in animals Good evidence of anxiolysis and reduced sedation Evidence of reduced sedation vs diazepam in humans Ocinaplon failed in Phase III, Alpidem withdrawn after licensing (both: liver toxicity)
51
what did olcinaplon and alpidem provide evidence of?
that it is possible to separate anxiolytic and sedative effects in humans
52
elevated plus maze quantifies
anxiety
53
what does the vogel water lick conflict test quantify
anxiety
54
what does the rotorod test quantify
motor activity
55
what does the morris water maze quantify?
memory
56
what is the vogel water-lick test?
In the Vogel test a rodent is deprived of water for 18 hours and then placed in a chamber with a water bottle. The animal will start to drink from the bottle, and the apparatus records the number of licks of the bottle. This is repeated on a subsequent day but on the third day, the animal is given a mild electric shock every 20 licks. It is now conflicted between satisfying its thirst and the fear of receiving a shock, which results in a decreased rate of licking. If the animal is given anxiolytic drugs it will not show as marked a decrease in the rate of licking because its fear will be diminished by the anxiolytic.
57
how is sedation measured
reduction in motor activity
58
how did BDZ binding site occur given it has no natural ligand
originally would haver been agonist binding sites but mutations accumulated mean that they can no longer bind GABA Happened to find a class of drug that fit into one of the redundant binding sites As it was originally an agonist binding site, it potentially retained some of the machinery that is in the ancestral agonist binding site and changes the conformational change that brings about channel opening??
59
knock out of alpha 6 subunit
a 6 has cerebellar expression compensatory expression other GABAA receptors + K channels - both inhibitory limited utility
60
knockout of beta 3 and gamma 2 GABA A subunits
perinatally lethal (death) limited utility
61
α105: conserved histamine residue H in α1,2,3,5
very high affinity for diazepam
62
α105: arginine (R) present in α4,6
very low affinity for diazepam
63
how to get low affinity for diazepam at a1, 2, 3, 5
mutate histidine to arginine H105R
64
mutation conserved a his to arg in BDZ
No change in GABA sensitivity No change in receptor assembly -expression levels of the receptor are completely normal Complete loss of classic BDZ binding -BZN binding site no longer has a high affinity for diazepam and compounds like flunitrazepam allows use of knock in transgenic animals
65
knock in
in vivo replacement of single amino acid in a defined gene
66
a1, a2, a3 histamine to arginine mutation knock in mice
generally normal phenotype normally responses to GABA
67
H-R knock in alpha 1
reduced amnesia reduced sedation increased anxiety A1 probably involved in amnesic and sedative effects
68
H-R knock in alpha 2
decreased anxiety increase sedation and amnesia alpha 2 probably involved in anxiolytic effects
69
treatment using a1 selevtive drugs?
sleeping tablets?
70
treatment using a2 selective drugs?
anti anxiety without sedation?
71
a3 subunit
a3 selective compounds anxiolytic in a2 know in mice is a3 also important?
72
TPA023B
zero efficacy at α1 but moderate efficacy at α2, 3 containing receptors. Anxiolytic in rodents and primates Not sedating in animals BUT!! Phase I trials (humans): highly sedating
73
reasons for failure of specific BDZs
Species differences between rodents/primates and man? Heterogeneity of alpha subunits within a receptor?

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