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Pharmacology Year 2 > Anxiolytics and hypnotics > Flashcards

Anxiolytics and hypnotics Flashcards

1
Q

Describe the synthesis of GABA in the pre-synaptic neurone

A

Glutamate (from the TCA) is converted to GABA (in the presynaptic neuron) via Glutamate Decarboxylase

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2
Q

State the two receptors that GABA can bind to when released into the synapse.
What does this binding lead to in each case?

A

GABA can bind to:
- GABA(a) receptors (Cl- ionophores) on the postsynaptic cell => hyperpolarisation

  • GABA(b) receptors (auto-rectpors) on pre-synaptic cell => regulation of GABA release into the synapse (similar to alpha2 receptors)
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3
Q

Describe the re-uptake and breakdown of GABA

A

GABA can then be re-up-taken by:
Glial cells
and/or
Pre-synaptic cell

In each case, GABA-Transaminase breaks down GABA into SSA (Succinic Semialdehyde).

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4
Q

In the metabolism of GABA, what is the Succinic Semialdehyde (SSA) converted into? By what enzyme?

A

Succinic Semialdehyde (SSA) is converted to Succinic Acid by Succinic Semialdehyde dehydrogenase (SSDH)

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5
Q

The enzymes involved in the synthesis and metabolism of GABA:

  • GAD
  • GABA-T
  • SSDH

Where are they found in the cell?

A

GAD is found in the cytosol whilst GABA-T and SSDH are found in the mitochondrial membrane.

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6
Q

Inhibitors of GABA metabolism leads to what?

Give examples of drugs which do this.

A

Inhibitors of GABA metabolism lead to more GABA and more inhibition in the brain.

e.g. Sodium Valproate, Vigabatrin

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7
Q

What are the four main proteins that make up the GABA-A receptor?

A

GABA receptor protein
Benzodiazepine receptor protein
Barbiturate receptor protein
Chloride channel protein (in the centre)

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8
Q

What protein links the GABA receptor protein and the benzodiazepine receptor protein?

A

GABA modulin

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9
Q

Describe the normal physiological action of GABA.

A
  • GABA binds to the GABA receptor protein
  • GABA modulin links the GABA receptor protein and the benzodiazepine receptor protein
  • This results in opening of the chloride ion channel
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10
Q

Name a competitive antagonist of the GABA receptor protein.

A

Biciculline

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11
Q

Name a competitive antagonist of the benzodiazepine receptor protein.

A

Flumazenil

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12
Q

What are the two main effects of benzodiazepines that facilitate GABA neurotransmission?

A
  • They facilitate the GABA-mediated opening of the chloride channel
  • They facilitate the binding of GABA to its receptor protein (increase the affinity of GABA to the GABA binding site) – this is reciprocated
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13
Q

What are the three main effects of barbiturates that facilitate GABA neurotransmission?

A
  • They enhance the normal physiological action of GABA
  • They enhance GABA binding to the GABA receptor protein (NOT reciprocated)
  • At higher concentrations, barbiturates can directly activate the chloride channel
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14
Q

What is the key difference in the mechanism of action of barbiturates and benzodiazepines?

A

Benzodiazepines – increase the frequency of chloride channel opening
Barbiturates – increase the duration of chloride channel opening

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15
Q

What is the relative difference in selectivity between barbiturates and benzodiazepines?

A

Barbs are less selective then BDZs so Barbs:

  • have less excitatory transmission.
  • are less safe (induce surgical anaesthesia and have a small therapeutic window)
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16
Q

List the clinical uses of benzodiazepines and barbiturates, give

A
  • Anaesthetics (barbiturates only = Thiopentone)
  • Anticonvulsants (Diazepam, Clonazepam, Phenobarbital)
  • Anti-spastics (Diazepam)
  • Anxiolytics
  • Sedatives/hypnotics
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17
Q

Define anxiolytic.

A

Remove anxiety without impairing mental or physical activity

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18
Q

Define sedative.

A

Reduce mental and physical activity without producing loss of consciousness

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19
Q

Define hypnotic.

A

Induces sleep

20
Q

Describe the general chemical structure of barbiturates

A
  • Six-membered ring structure (4 carbons and 2 nitrogens)
  • 2 R groups;
    R1 = ethyl
    R2 = phenyl/1-methylbutyl.
21
Q

Barbiturates have been largely superseded by benzodiazepines. Which barbiturate is still used relatively commonly as a sedative/hypnotic? State an unwanted effect of using this drug?

A

Amobarbital

Causes severe intractable insomnia.

22
Q

What is the half-life of amobarbital?

A

20-25 hours

23
Q

Barbiturates have many unwanted effects so are not a 1st line;
List some of their unwanted effects.

A

Small therapeutic window => depress respiration.
Reduce REM sleep (=> “hangovers”/irritability)
Enzyme inducers
Potentiate effects of other CNS depressants (e.g. alcohol)
Tolerance and dependence

24
Q

Describe the chemical structure of benzodiazepines

A

Usually a triple-ring structure.

25
Q

What do all BZDs act on? What determines which BZD is used clinically?

A

All act on GABA-A receptors, have similar potencies but it’s the pharmacokinetics that differentiate use

26
Q

Describe the administration of benzodiazepines.

A

Well absorbed per orally

Peak plasma concentration after about 1 hour

27
Q

When would you give IV benzodiazepines?

A

Treatment of status epilepticus

28
Q

Describe the distribution of benzodiazepines.

Highly lipid soluble

A

Bind strongly to plasma proteins

29
Q

Describe the metabolism of benzodiazepines.

A

Extensively metabolised in the liver

30
Q

Describe the excretion of benzodiazepines.

A

Excreted in the urine as glucuronide conjugates

31
Q

Describe the duration of action of benzodiazepines.

A

Varies a lot

This allows classification as short-acting and long-acting benzodiazepines

32
Q

What makes long-acting benzodiazepines have a long duration of action?

A

They have slower metabolism
and/or
They generate active metabolites

33
Q

Name two short-acting benzodiazepines.

A

Oxazepam

Temazepam

34
Q

Name a long-acting benzodiazepine.

A

Diazepam

35
Q

Describe the metabolism of oxazepam.

A

It is metabolised straight to its glucuronide conjugate (t1/2 = 8 hours)

36
Q

Describe the metabolism of temazepam.

A

Metabolised to oxazepam and then to the glucuronide conjugate

37
Q

Describe the metabolism of diazepam.

A

Metabolised via temazepam and oxazepam to the glucuronide conjugate

Some diazepam is metabolised to nordiazepam and then oxazepam

38
Q

Name three drugs that are used as anxiolytics.

A

General rule – long-acting benzodiazepines
Diazepam
Chlordiazepoxide
Nitrazepam

39
Q

Under what condition would you use a short-acting benzodiazepine as an anxiolytic?

A

Hepatic impairment – this means that the benzodiazepines will be metabolised more slowly
Drug of choice = oxazepam

40
Q

Name two drugs that are used as sedatives/hypnotics.

A

General rule – short-acting benzodiazepines
Oxazepam
Temazepam

41
Q

Name a long acting drug that might be used as a sedative/hypnotic.

A

Nitrazepam (t1/2 = 28 hours)

42
Q

What are the unwanted effects of benzodiazepines?

A

Sedation
Confusion
Ataxia
Potentiate other CNS depressants (e.g. alcohol)
Tolerance
Dependence
Free plasma concentration of benzodiazepines can be increased by giving aspirin and heparin

43
Q

What are the advantages of benzodiazepines over barbiturates?

A

Wide margin of safety;

  • Overdose causes prolonged sleep (but this is rousable)
  • Flumezanil can be given IV if a patient has overdosed
  • Mild effect on REM sleep
  • Do NOT enhance liver enzymes
44
Q

Name a sedative/hypnotic that isn’t a benzodiazepine. What class of drug does this fall into?

A

Zopiclone;

  • cyclopyrrolone
  • short-acting (t1/2 = 5 hours)
  • acts on the benzodiazepine receptor but it is not a benzodiazepine
  • has fewer hangover effects but dependency is still an issue
45
Q

What drug is used to control the physical symptoms of anxiety?

A

Propranolol

46
Q

Name a new drug that has started being used as an anxiolytic.

A

Buspirone – 5HT1A agonist
This has relatively few side effects and causes less sedation than benzodiazepines
Downside: slow onset of action (maximal anxiolytic effects are not seen for a number of days/weeks)

Pharmacology Year 2 (32 decks)

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