Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Drugs And The Brain > anxiolytics > Flashcards

anxiolytics Flashcards

You may prefer our related Brainscape-certified flashcards:
The Brain flashcards
1
Q

barbiturates (derivatives of barbital)

A

amobarbital
pentobarbital
thiopental
phenobarbital

-note al ending (also see -one ending)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

historical uses of barbiturates

A

Anxiolytics
Anticonvulsants
Sedatives/hypnotics
Anaesthetics

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

barbiturates and overdose

A

very dangerous in overdose

respiratory depression

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

when are barbiturates used as anxiolytics and anticonvulsants

A

in extreme cases

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

when are barbiturates used as anaesthetics?

A

for induction or very short procedures

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

why are barbiturates so dangerous in overdose?

A

because they can directly activate GABA receptors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

general mechanism of action or barbiturates

A

boost inhibitory transmission

can decrease excitatory transmission

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

lethal injection common cocktail

A

sodium thiopental
pancuronium bromide
potassium chloride

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

purpose of sodium thiopental in lethal injection cocktail

A

induce loss of consciousness and repress respiratory drive

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

replacement drugs for lethal injection used since 2011

A

using pentobarbital or a benzodiazepine/ opioid mixture as a replacement

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

why did benzodiazepines replace barbiturates?

A

because they are safer in overdose

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

what was the first barbiturate synthesised?

A

chlordiazepoxide

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

effects of benzodiazepines

A

anxiolytic

sedative

muscle relaxant

amnesic

anticonvulsant

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

why are barbiturates use sparingly

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

where is the benzodiazepine binding site on GABA A?

A

on the interfaces of alpha 1 and gamma 2

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

benzodiazepine agonists

A

flunitrazepam
diazepam
temazepam
nitrazepam

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

mechanism of benzodiazepine agonists

A

increase GABA a receptor channel opening frequency

can also increase affinity for GABA binding sites

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

benzodiazepine

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

what is flumazenil used for?

A

to block potentiation by flunitrazepam

therefore used to reverse benzodiazepine sedation (overdose)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

benzodiazepine inverse agonists

A

B carbolines (DMCM)

proconvulsant
anxiogenic

decrease channel opening frequency

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

what can block the action of B carbolines

A

by flumazenil

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

SAM meaning

A

silent allosteric modulator

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

Two distinct CNS populations defined by binding studies

A

CL218-872:
High affinity for Cl: Type I benzodiazepine binding sites
Low affinity for Cl: Type II

differ in regional distribution
receptor heterogeneity?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

benzodiazepine and alpha 1 subunit

A

type 1 BDZ binding site - binds classic BDZs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

benzodiazepine and alpha 2, 3, 5 subunit

A

type II BDZ binding site - binds classic BDZs

31
Q

benzodiazepine and alpha 4, 6 subunit

A

high affinity for Ro 15-4513, but not for classic BDZs

32
Q

Ro compound

A

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
Q

what does pharmacology of benzodiazepine binding site depend on?

A

the alpha subunit at the alpha gamma interface of a GABA A receptor

34
Q

use of BDZ when first introduces

A

first line treatments for anxiety and sleep disorders

also frequently used as anticonvulsants

35
Q

what are most BDZ used for today?

A

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
Q

use of midazolam

A

sedative for minor surgical procedure

37
Q

use of chlordiazepoxide

A

to aid with alcohol withdrawal

38
Q

use of clobazam and clonazepam

A

treatment of epilepsy

39
Q

use of diazepam

A

treat muscle spasms

40
Q

what are the z deugs

A

zaleplon
zopiclone
zolpidem

41
Q

what are z drugs used for

A

primarily for the treatment of sleep disorders
-hypnotics or sleeping tablets

42
Q

features of z drugs

A

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
Q

oppositional tolerance model with reference to benzodiazepines

A

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
Q

tolerance and dependence with BDZ

A

Can develop rapidly and this is one of the reasons that they are recommended only for short term use (28 days maximum)

45
Q

withdrawal effects BDZ

A

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
Q

why do we want to develop anxioselective BDZ ligands?

A

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
Q

drugs in first wave of studies

A

bretazenil

alpiden and ocinaplon

48
Q

bretazenil

A

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
Q

interaction between bretazenil ethanol

A

found to be stronger than that of ethanol and diazepam

50
Q

alpidem, ocinaplon

A

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
Q

what did olcinaplon and alpidem provide evidence of?

A

that it is possible to separate anxiolytic and sedative effects in humans

52
Q

elevated plus maze quantifies

A

anxiety

53
Q

what does the vogel water lick conflict test quantify

A

anxiety

54
Q

what does the rotorod test quantify

A

motor activity

55
Q

what does the morris water maze quantify?

A

memory

56
Q

what is the vogel water-lick test?

A

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
Q

how is sedation measured

A

reduction in motor activity

58
Q

how did BDZ binding site occur given it has no natural ligand

A

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
Q

knock out of alpha 6 subunit

A

a 6 has cerebellar expression

compensatory expression other GABAA receptors + K channels
- both inhibitory

limited utility

60
Q

knockout of beta 3 and gamma 2 GABA A subunits

A

perinatally lethal (death)

limited utility

61
Q

α105: conserved histamine residue H in α1,2,3,5

A

very high affinity for diazepam

62
Q

α105: arginine (R) present in α4,6

A

very low affinity for diazepam

63
Q

how to get low affinity for diazepam at a1, 2, 3, 5

A

mutate histidine to arginine
H105R

64
Q

mutation conserved a his to arg in BDZ

A

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
Q

knock in

A

in vivo replacement of single amino acid in a defined gene

66
Q

a1, a2, a3 histamine to arginine mutation knock in mice

A

generally normal phenotype

normally responses to GABA

67
Q

H-R knock in alpha 1

A

reduced amnesia
reduced sedation
increased anxiety

A1 probably involved in amnesic and sedative effects

68
Q

H-R knock in alpha 2

A

decreased anxiety
increase sedation and amnesia

alpha 2 probably involved in anxiolytic effects

69
Q

treatment using a1 selevtive drugs?

A

sleeping tablets?

70
Q

treatment using a2 selective drugs?

A

anti anxiety without sedation?

71
Q

a3 subunit

A

a3 selective compounds anxiolytic in a2 know in mice
is a3 also important?

72
Q

TPA023B

A

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
Q

reasons for failure of specific BDZs

A

Species differences between rodents/primates and man?

Heterogeneity of alpha subunits within a receptor?

Drugs And The Brain (9 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions