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Y2 Pharm (LCRS1) > Anxiolytics and Hypnotics > Flashcards

Anxiolytics and Hypnotics Flashcards

1
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

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2
Q

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

A

GABA modulin

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3
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 trasnient opening of the chloride ion channel

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4
Q

Name a competitive antagonist of the GABA receptor protein.

A

Biciculline

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5
Q

Name a competitive antagonist of the benzodiazepine receptor protein.

A

Flumazenil

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6
Q

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

A

They enchance the action of 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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7
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 have a direct action on the chloride channel

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8
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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9
Q

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

A

Barbiturates are LESS selective

This may explain why barbiturates induce surgical anaesthesia and why barbiturates are less safe than benzodiazepines

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10
Q

Name a barbiturate that is used as an anaesthetic.

A

Thiopentone

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11
Q

Name three barbiturates and benzodiazepines that are used as anti-convulsants.

A

Diazepam (BDZ)
Clonazepam (BDZ)
Phenobarbital (BARB)

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12
Q

Name a benzodiazepine that is used as an anti-spastic.

A

Diazepam

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13
Q

What are the clinical uses of benzodiazepines and barbiturates?

A 
Anaesthetics (BARBs only)
Anticonvulsants
Anti-spastics
Anxiolytics 
Sedatives/Hypnotics
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14
Q

Define anxiolytic.

A

Remove anxiety without impairing mental or physical activity

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15
Q

Define sedative.

A

Reduce mental and physical activity without producing loss of consciousness

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16
Q

Define hypnotic.

A

Induces sleep

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17
Q

What structure is common to all barbiturates?

A

Six-membered ring (4 carbons and 2 nitrogens)

Differ in R1 R2 and X substituants

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18
Q

Barbiturates have been largely superseded by benzodiazepines. Which barbiturate is still used relatively commonly and what for?

A

Amobarbital

As a sedative/hypnotic

Induces severe intractable insomnia

Usually only if patient isn’t responding to benzodiazepines

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19
Q

What is the half-life of Amobarbital?

A

20-25 hours

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20
Q

What are the unwanted effects of barbiturates?

A

Low safety margin (overdose can be lethal)

Alters natural sleep (reduced REM)

Enzyme inducers

Potentiate the action of other CNS depressants (e.g. alcohol)

Tolerance (tissue and pharmacokinetic)

Dependence

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21
Q

What structure is common to all benzodiazepines?

A

They have a three ring structure (tricyclic)

Differ in their 4 substituant groups

Relativley small changes in all the groups

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22
Q

What are the three key benzodiazepines?

A

Diazepam
Oxazepam
Temazepam

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23
Q

What is the difference between all the benzodiazepines that are in clinical use?

A

Their pharmacokinetics

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24
Q

Describe the administration of benzodiazepines.

A

Well absorbed per orally

Peak plasma concentration after about 1 hour

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25
Q

When would you give IV benzodiazepines?

A

Treatment of status epilepticus (tonic clonic seizure lasting more than 30 minutes - medical emergency)

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26
Q

Describe the distribution of benzodiazepines.

A

Bind strongly to plasma proteins

Highly lipid soluble

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27
Q

Describe the metabolism of benzodiazepines.

A

Extensively metabolised in the liver

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28
Q

Describe the excretion of benzodiazepines.

A

Excreted in the urine as glucuronide conjugates

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29
Q

Describe the duration of action of benzodiazepines.

A

Varies a lot

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

30
Q

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

A

They have slower metabolism

They generate active metabolites

31
Q

Name two short-acting benzodiazepines with their half lives.

A

Oxazepam
Temazepam
(t1/2 = 8 hours)

32
Q

Name a long-acting benzodiazepine and its glaf life.

A

Diazepam

t1/2 = 32 hours

33
Q

Describe the metabolism of oxazepam.

A

It is metabolised straight to its glucuronide conjugate

34
Q

Describe the metabolism of temazepam.

A

Metabolised to oxazepam and then to the glucuronide conjugate

35
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

Note:
nordiazepam has some Benzodiazepine activity

36
Q

Name three drugs that are used as anxiolytics.

A

General rule – long-acting benzodiazepines
Diazepam
Chlordiazepoxide
Nitrazepam

37
Q

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

A

Hepatic impairment – this means that the benzodiazepines and metabolised more slowly – drug of choice = oxazepam

38
Q

Name two drugs that are used as sedatives/hypnotics.

A

General rule – short-acting benzodiazepines
Oxazepam
Temazepam

39
Q

Name a long acting drug that might be used as a sedative/hypnotic. Why would it be used?

A

Nitrazepam (t1/2 = 28 hours)

Used if they have anxiety during the day as well or if they have problems with waking up too early in the morning

40
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

41
Q

What are the unwanted effects of benzodiazepines?

A

Sedation

Confusion

Ataxia

Amnesia

Potentiate other CNS depressants (e.g. alcohol)

Tolerance (tissue only)

Dependence - withdrawal less intense than BARBs

Free plasma concentration of benzodiazepines can be increased by giving aspirin and heparin

42
Q

How does zopiclone work?

A

Used as a sedative/hypnotic

Acts on the benzodiazepine receptor but isnt a BDZ its a

This has fewer hangover effects but dependency is still an issue

43
Q

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

A

Propranolol

Beta blocker that prevents:
TACHYCARDIA (beta1)
TREMOR (beta2)

44
Q

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

A

Buspirone – 5HT1A agonist

45
Q

Describe the morphology of GABA neurones.

A

They are generally short inhibitory interneurons

46
Q

Where do you find longer GABA tracts?

A

Striato-nigral (Striatum to substantia nigra)

Cerebellar

47
Q

What is the main action of GABA neurones?

A

Widespread inhibitory action in the CNS

48
Q

How is GABA synthesised?

A

Glutamate is converted to GABA by GABA decarboxylase

49
Q

What does GABA decarboxylase need for optimal activity?

A

Vitamin B6

50
Q

What does GABA act on?

A

Stimulates the GABAa receptor - a type 1 receptor cholride ionophore

Often found on Glutaminergic, dopaminergic and 5HT neurones

51
Q

What is glutamate?

A

An amino acid

Single most excitatory neurotransmitter in the brain

52
Q

How is GABA neutralized?

A

Primarily by re-uptake into glial cells or presynaptic terminal

Metabolised by GABA-T (GABA transaminase) to SSA (Succinic semialdehyde)

53
Q

What is the function of the GABAb receptor?

A

Sits on the pre synaptic terminal

Acts like the alpha 2 receptor in adrenergic synapses

‘Auto-receptor’ - when levels of GABA get high in the synapse it acts as a negative feedback system to reduce GABA release into the synapse

54
Q

Where is GAD found?

A

This enzyme is exclusive to GABA nerve terminals – it is a marker for GABA neurones

55
Q

How is GABA released from the presynaptic terminal?

A

Calcium-mediated exocytosis in vesicles

56
Q

How is GABA metabolised?

A

GABA converted to Succinic semialdehyde by GABA transaminase (GABA-T)

Succinic semialdehyde converted to succinic acid by succinic semialdehyde dehydrogenase (SSDH)

57
Q

Where are the enzymes of GABA metabolism found?

A

Mitochondrial membrane

58
Q

What is the GABA shunt?

A

the product of GABA metabolism (Succinic acid) goes into the TCA cycle

Glutamate is generated from the TCA

Glutamte then goes to make GABA which is eventually metabolised back into Succinic acid

59
Q

Where is GAD found in the cell?

A

In the cytoplasm

60
Q

What are 2 drugs that inhibit GABA metabolism?

A

Sodium Valproate - covalently binds to GABA-T a ‘Suicide inhibitor’

Valproate - inhibits both GABA-T and SSDH. Also possibly reduced glutmate release from neurones

61
Q

What is flumazenil used for?

A

Reversal of benzodiazepine overdose

It has affinity but no efficacy for the BDZ receptor as acts as a competitive inhibitor

62
Q

Other than their action at the GABAa receptor, what other actions do Barbiturates have?

A

Reduce the activity of glutamate receptors, therefore reduce excitatory transmittion

63
Q

What is meant by allosteric?

A

Barbiturates and benzodiazepines bind to a different site than GABA on the same receptor

64
Q

What is the difference between a sedative and a hypnotic?

A

The same drugs are used

Hypnotics are just at higher doses of the drug

65
Q

Why is phenobarbital not sued much anymore?

A

It has many side effects

66
Q

What does Diszepam have its action on?

A

Alpha motor neurones in the spinal cord - caused muscle relaxation

67
Q

Why is thiopentone used as an aneasthetic?

A

It has a very rapid action as it is very lipid soluble

68
Q

What’s the class and half life of zopiclone?

A

cyclopyrrolone

It’s short-acting (t1/2 = 5 hours)

69
Q

What are the positive and negative effects of zopicone?

A

Positive:
Minimal hangover effects

Negative:
Dependency still an issue

70
Q

What are the positive and negative effects of buspirone?

A

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)

Y2 Pharm (LCRS1) (34 decks)

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