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LCRS Pharma > Anxiolytics, Sedatives and Hypnotics > Flashcards

Anxiolytics, Sedatives and Hypnotics Flashcards

1
Q

what is the main inhibitory neurotransmitter in the CNS?

A

GABA

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2
Q

what is GABA derived from?

A

glutamate (happens to be the excitatory neurotransmitter of CNS also)

conversion via Glutamate Decarboxylase (GAD) during the GABA shunt
GAD found in cytosol

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3
Q

where does GABA bind post-synaptically? what effect does this have?

A

GABAa receptor

hyperpolarises the cell by Cl- influx

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4
Q

where does GABA bind pre-synaptically? what effect does this have?

A

GABAb receptor (autoreceptor)

regulates the release of GABA (inhibition of release)

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5
Q

which two locations can GABA be reuptaken?

A

1) at glial cells (found lateral to the pre-synaptic neurone)
2) the pre-synaptic neurone itself

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6
Q

what breaks down GABA in glial cells and pre-synaptic neurones?

A

GABA-Transaminase

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7
Q

what is GABA broken down into by GABA-T?

A

Succinic Semialdehyde

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8
Q

what is succinic semialdehyde broken down into? by what?

A

succinic acid

by succinic semialdehyde dehydrogenase

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9
Q

what is overall formation and deactivation pathway of GABA?

A

formation:
- Glutamate
- GABA
(via glutamate decarboxylase)

metabolism:
- succinic semialdehyde
(via GABA transaminase)
- succinic acid
(via succinic semialdehyde dehydrogenase)

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10
Q

where is GAD found?

A

found in the cytosol

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11
Q

where is GABA-T and SSDH found?

A

found in the mitochondrial membrane.

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12
Q

how can the action of GABA be enhanced?

A

1) by using Inhibitors of GABA metabolism
- ->so GABA is increased leading to more inhibition in the brain

2) by stimulating GABA receptors (increasing Cl- influx)
- use of barbs and BDZs

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13
Q

what are examples of inhibitors of GABA metabolism?

A

Sodium Valproate (epilim) Vigabatrin (sabril)

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14
Q

what is sodium valproate used for?

A

anti-convulsive i.e. epileptic seizures

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15
Q

what is vigabatrin used for?

A

epilepsy where GABA inhibition is not at its optimal

reduce GABA metabolism

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16
Q

how does sodium valproate work?

A

inhibitor of GABA metabolism:
it is a weak inhibitor of GABA-T and SSDH
nb GABA-T and SSDH are found in the mitochondria

also binds to sodium channels
has a complex MoA

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17
Q

how does vigabatrin work?

A

inhibitor of GABA-T therefore metabolism

binds covalently, therefore irreversibly

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18
Q

what are the 4 proteins that make up GABAa receptor (post-synaptic)?

A

o GABA receptor Protein.
o GABA modulin.
o Barbiturate receptor protein.
o BDZ (Benzodiazepine) receptor protein.

there is a chloride channel protein in the middle

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19
Q

what is the effect of GABA on the Chloride channel?

A

the domains are linked so

opens the Cl-channel causing hyperpolarisation of the membrane

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20
Q

what is the effect of BDZ binding to GABAa?

A

binds to BDZ receptor protein

  • this enhances the GABA affinity
  • leads to chloride influx and therefore hyperpolarisation
  • the binding of GABA improves BDZ binding aswell (reciprocity)
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21
Q

what is the effect of Barbs biding to GABAa?

A

enhances GABA’s

but the action is not reciprocated by GABA for Barbs

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22
Q

what effect does higher concentrations of Barbs have on the GABAa receptor?

A

has a direct activating effect on the Cl- channel (like GABA can aswell)

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23
Q

Name competitive antagonists of GABA and BDZs for GABAa receptor

A
  • Bicuculline compete with GABA

- Flumazenil compete with BDZ

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24
Q

what overall effect do BZDs have on GABAa Chloride channel?

A

increases the frequency of its opening

[BDZ treat convulsions with frequent spasms]

25
Q

what overall effect do Barbs have on GABAa chloride channel?

A

increase the duration of its opening

[barbed fences–> more time in jail]

26
Q

why do barbs cause less excitatory transmission that BDZs? what does this mean for barbs?

A

they are less selective

this means barbs are more dangerous and have more dangerous side effects: small therapeutic window (low safety margin)

27
Q

what does the low selectivity of barbs enable its usage for?

A

induction of surgical anaesthesia

28
Q

what role does GABA play for the action of Barbs and BDZs?

A

They are not independent of GABA, GABA is required for their MoA

29
Q

how can you describe barbs and BDZ in terms of binding to GABA?

A

allosteric

30
Q

what is used for anaesthetics?

A

Barbiturates only

– e.g. Thiopentone.

31
Q

what can be used as anti-convulsants?

A

Diazepam, Clonazepam, Phenobarbital.

32
Q

what can be used as anti spastics?

A

Diazepam (into spinal cord to reduce muscle tone)

33
Q

what are the uses of BDZs and barbs?

A

o Anaesthetics (Barbs only)
o Anticonvulsants (both)
o Anti-spastics (both)
o Anxiolytics (“Long-acting”, BDZs only)
o Sedatives/Hypnotics (“Short-acting”; both)

34
Q

what are anxiolytics?

A

remove anxiety without impairing mental or physical activity.

35
Q

what are sedatives?

A

reduce mental and physical activity without producing a loss of consciousness

36
Q

what are hypnotics?

A

induce sleep.

37
Q

what is the order of drugs in order of decreasing wakefulness?

A

anxiolytics
sedatives (higher dose has hypnotic effect)
hypnotics

38
Q

what would the ideal properties of anxiolytics,

sedatives and hypnotics be?

A
  • have a large therapeutic window, high safety margin
  • not depress respiration
  • produce natural sleep
  • not interact with other drugs
  • low drowsiness
  • not produce “dependence”.
39
Q

describe Barbiturates structure

[-tone, -tol, -tal]

A
  • tend to have a single ring structure with two R-groups and an X group
  • R groups are – ethyl groups and phenyl/1-methylbutyl
  • a sedative/hypnotic effect
40
Q

amobarbital and its use

A

Amobarbital for severe intractable insomnia

T1/2 = 20-25h

41
Q

what are the unwanted side effects of Barbs leading to it being superseded by BDZs?

A

o Small therapeutic windows – depress respiration.
o Reduce REM sleep
- “hangovers”
o Induce enzymes (chronic use) so co-administration needs to be careful
o Potentiate effects of other CNS depressants
– alcohol so OD is easier
o Tolerance and dependence become issues (withdrawal syndrome)

42
Q

describe benzodiazepines [-epam, -epate] structure

A
  • Usually a triple-ring structure (R1-R4)
  • bind to all GABAa receptors
  • different drugs have difference pharmacokinetics so that determines their use (duraction of action varies)
43
Q

describe the pharmacokinetic of BDZs

A

o Administration
– orally or IV, peak plasma at ~1h.
o Binds plasma proteins strongly, high lipid solubility.
o Extensive liver metabolism.
o Excretion – urine (glucuronide conjugates).
o Duration of action – varies greatly

44
Q

how do BDZs vary in duration of action?

A

there are long acting and short acting BDZs

long acting BDZs have slower metabolism and/or active metabolites–> use as anxiolytics

45
Q

give examples of long acting BDZs

A

locating acting drugs used for anxiolytic effect

  • diazepam (valium) 32h
  • nitrazepam 28h
  • Chlordiazepoxide (Librium) 12h

nitrazepam due to long DOA can be used as a hypnotic at night and anxiolytic by day at the same time

46
Q

give examples of short acting BDZs

A
  • Temazepam (becomes oxazepam) 8h
  • Oxazepam 8h–> liver impairment anxiolytic however
  • Lorazepam 12h

these get into the urine quickly

NB anxiolytics need long acting drugs

47
Q

what BDZ should be given to those with hepatic impairment?

A

Oxazepam (short acting)

impaired liver will take longer to metabolise the oxazepam so the half-life will be longer

48
Q

what BDZ is given for a hypnotic effect at night

followed by an anxiolytic effect during the day (daytime anxiety)?

A

Nitrazepam (long acting)

will have a longer effect, not just for the night

49
Q

what is the final excreted product of BDZs?

A

glucuronide conjugates

50
Q

what is the advantage of using BDZs over Barbs in terms of overdose?

what is the antidote for reversal?

A

has a wider therapeutic window so an overdose leads to just prolonged sleep i.e. safer in overdose

An antidote is available:
Flumazenil (BDZ antagonist)
can reverse effect

51
Q

what other advantages are there to using BDZs over barbs?

A

o Mild effect on REM sleep.
o Does not induce liver enzymes.

unlike barbs

52
Q

what are the unwanted effects of BDZs?

A

o Sedation, confusion, amnesia, ataxia
– all impaired manual skills.

o Potentiates other CNS depressants.

o Tolerance (less than barbs and includes “tissues only”)

o Dependence (less intense than barbs).

o Free plasma concentration increases when co-administered with aspirin, heparin.

53
Q

What is Zopiclone? describe it use and effects

A
  • short acting cyclopyrrolones
  • sedative/hypnotic
  • bind to BDZ receptor protein(NOT a BDZ however)
  • minimal hangover effects
  • dependency issue
54
Q

what is an advantage and disadvantage of SSRIs as antidepressants?

A

A: less sedation and dependence, safer in OD

D: have a delayed response (a week), not effective against more severe condition

55
Q

name anti-epileptics

A
  • Valproate (GABA-T inhibitor)
  • Tiagabine (GABA reuptake inhibitor GAT-1)

these enhance GABA transmission

56
Q

name anti-psychotics

A

Olanzapine

Quetiapine

57
Q

what can be used to treat the physical symptoms of anxiety?

A

beta blocker propranolol

58
Q

name a drug for anxiety disorder

A

Buspirone
– 5HT1A-Receptor agonist (serotonin)

  • with fewer side effects (less sedation)
  • but has a slow onset of action.
59
Q

what type of drug is used to treat insomnia?

A

BDZ like temazepam

LCRS Pharma (32 decks)

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