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Yr 2 LCRS - Pharm > 26 - Anxiolytics & Hypnotics > Flashcards

26 - Anxiolytics & Hypnotics Flashcards

1
Q

Summarise GABA Neurotransmission

A

Precursor is glutamate

Glutamate is converted by glutamate decarboxylase (GAD) to form GABA

  • GAD needs vitamin B6 as its co-enzyme

GABA stored in vesicles in pre-synaptic terminals

Action potential arrives in short axon

Depolarisation

Influx of calcium

Exocytotic release of GABA into synaptic cleft

GABA diffuses across cleft

GABA stimulates post-synaptic receptors

  • these are chloirde ionophore receptors
  • GABAA receptors
  • these are type 1 receptors (ion-channel linked)
  • these sit on the post-synaptic neurones (often glutamatergic, but could be any other neurone)

GABA is regulating the activity of the post-synaptic neurone

Chloride ions flow into the post-synaptic neurone, hyperpolarisation (around -90mV)

Neurone is more difficult to excite

GABA is mainly removed by synapse by reuptake

  • into glial cells or into pre-synaptic neurone

Then is metabolised

  • by GABA transaminase

GABAB receptors are mainly pre-synaptic and are mainly regulatory

  • if too much GABA release, it acts on these receptors
  • this causes less GABA release
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2
Q

Outline GABA metabolism

A

GABA is firstly reuptaken

Then acted on by catabolic enzymes

Succinic acid is final product

  • then goes into TCA cycle in glial cells

GAD is a cytoplasmic enzyme

  • only in GABAergic neurones

GABA-T and SSDH are mitochondrial enzymes

Sodium Valproate and Vigabatrin are anti-convulsant drugs and then inhibit GABA metabolism. Raise central GABA levels.

Vigabatrin acts on GABA-T only (covalently)

Sodium Valproate acts on GABA-T and SSDH at therapeutic concentrations. Also, acts on VSSCs so can reduce glutamate release

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3
Q

Describe the structure of the GABAA Receptor Complex

A

4 main proteins

  • GABA receptor protein
  • Barbiturate receptor protein
  • Chloride channel protein
  • Benzodiazepine receptor protein

When GABA binds:

  • binds to GABA receptor protein
  • causes linkage between GABA receptor protein and BDZ receptor protein
  • mediated by GABAmodulin peptide
  • this causes transient open of chloride channel
  • causes hyperpolarisation

When BDZs bind:

  • bind to BDZ receptor protein
  • enhance the opening of the channel
  • also, in the presence of a BDZ, there is a better binding of GABA to the receptor. this is reciprocated and causes better binding of BDZ

When Barbituates bind:

  • binds to barbituate receptor protein
  • enhances normal action of GABA
  • also in presence of a barbituate, there is better binding of GABA but this is not reciprocated
  • at higher doses, they can cause direct opening of chloride channel

Bicuculline:

  • competitive GABA receptor antagonist

Flumazenil:

  • competitive BDZ antagonist
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4
Q

What effect do BDZs and BARBs have on the GABAA Receptor Complex?

A

Have no direct action on GABA

Need GABA to be present in order to work

Allosteric action - have their own binding sites of GABAA receptor

BARBs less selective than BDZs

  • BARBs may also reduce exictatory transmission, antagonist effects at glutamate receptors
  • BARBs can induce social anaesthesia
  • BARBs have relatively low margin of safety

BDZs = increase frequency of opening of chloride channel

BARBs = increase duration of chloride channel opening

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5
Q

What are the clinical uses of …?

A

Anaesthetics - BARBs only

  • thiopentone
    • inducing agent
    • very highly lipid soluble

Anticonvulsants

  • diazepam
    • epilepsy
  • clonazepam
    • epilepsy
  • phenobarbital
    • less used because of side-effects

Anti-Spastics

  • diazepam
    • relaxation of tension

Anxiolytics

Sedatives/Hypnotics

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6
Q

Define ‘Anxiolytics’

A

ANXIOLYTICS

Remove anxiety without impairing mental or physical activity

‘Minor Tranquilisers’

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7
Q

Define ‘Sedatives’

A

SEDATIVES
Reduce mental and physical activity without producing loss of consciousness

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8
Q

Define ‘Hypnotics’

A

HYPNOTICS

Induce sleep

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9
Q

What characteristics should anxiolytics, sedatives and hypnotics ideally all have?

A

Ideally they should:

i) HAVE WIDE MARGIN OF SAFETY
ii) NOT DEPRESS RESPIRATION
iii) PRODUCE NATURAL SLEEP (HYPNOTICS)
iv) NOT INTERACT WITH OTHER DRUGS
v) NOT PRODUCE ‘HANGOVERS’
vi) NOT PRODUCE DEPENDENCE

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10
Q

Describe the molecular structures of barbiturates

A

6 membered ring

Differ in R1, R2 and X

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11
Q

What are the clinical uses of barbiturates?

A

Range of clinical uses including

  • sedative/hypnotic
    • amobarbital
    • severe intractable insomnia
    • half life = 20-25 hours
    • intermediate acting BARB
    • superceded by BDZs, not gold-standard
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12
Q

What are the unwanted effects of barbiturates?

A

UNWANTED EFFECTS OF BARBITURATES

NOT 1ST LINE DRUGS

Low Safety Margins

  • depress respiration
  • overdosing lethal

Alter Natural Sleep

  • low REM
  • lead to hangovers and irritability

Enzyme Inducers

Potentiate Effects of Other CNS Depressants

  • e.g. alcohol

Tolerance

Dependence

  • withdrawal syndrome
  • insomnia, anxiety, tremore, convulsions, death
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13
Q

Describe the molecular structures of Benzodiazepines

A

Three-ring structure

Different substituent groups

  • relatively small changes between different BDZs leads to big changes in pharmacokinetics

Flumazenil

  • antagonist of BDZs
  • similar structure to BDZs
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14
Q

How many Benzodiazepines are available and where do they act?

A

Around 20 available

All act at GABAA Receptors

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15
Q

What determines the use of different Benzodiazepines?

A

All have similar potencies and profiles

Pharmacokinetics largely determine use

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16
Q

Outline the administration of Benzodiazepines

A

ADMINISTRATION

Well absorbed

Peak plasma concentration is at around 1 hour after administration

IV for status epilepticus as it is a medical emergency

17
Q

Outline the distribution of Benzodiazepines

A

DISTRIBUTION

Bind plasma proteins strongly

Highly lipid soluble and are therefore widly distributed

18
Q

Outline the metabolism of Benzodiazepines

A

METABOLISM

Usually extensive - especially in the liver

  • Short-Acting (Temazepam, Onazepam)
  • Long-Acting (Diazepam)
    • converted to active metabolites to make it long-acting
19
Q

Outline the excretion of Benzodiazepines

A

EXCRETION

URINE: Glucuronide conjugates

20
Q

Outline the duration of action of the Benzodiazepines

A

DURATION OF ACTION - VARY GREATLY

Short-Acting

Long-Acting

  • slow metabolism and/or active metabolites
21
Q

What are the advantages of Benzodiazepines?

A

Wide margin of safety (better than BARBs)

  • overdose = prolonged sleep (rousable)
  • flumazenil = antagonist
  • only mild effect on REM sleep
  • do not induce liver enzymes
22
Q

Give examples of anxiolytic Benzodiazepines

A

ANXIOLYTICS (‘long-acting’)

  • Diazepam (Valium)
  • Chlorodiazepoxide (Librium)
  • Nitrazepam

NOTE: Oxazepam

  • 8 hour half-life
  • hepatic impairment
  • shorter-acting
23
Q

Give examples of sedative/hynoptics Benzodiazepines

A

SEDATIVE/HYPNOTIC BENZODIAZEPINE - ‘short acting’

  • Temazepam
  • Oxazepam

NOTE:

  • Nitrazepam - 28 hour half-life - daytime anxiolytic effect
24
Q

Outline the unwanted effects of Benzodiazepines

A

UNWANTED EFFECTS

Sedation

Confusion

Amnesia

Ataxia (impaired manual skills)

Potentiate other CNS depressants (alcohols, barbiturates)

Tolerance

  • less than barbiturates
  • ‘tissue’ only

Dependence

  • withdrawal syndrome similar to barbiturates but less intense
  • withdraw slowly

Free Plasma Concentration is high

  • e.g. aspirin, heparin
25
Q

State another sedative/hynoptic not mentioned

A

ZOPICLONE

Short Acting

  • 5 hour half-life

Acts at Benzodiazepine Receptors

  • cyclopyrolone

Similar efficacy to benzodiazepines

Minimal hangover effects but dependency still a problem

26
Q

State some other anxiolytics not mentioned

A

ANXIOLYTICS

ANTI-DEPRESSANT

SSRIs

  • less sedation and dependence
  • delayed response
  • long-term treatment

ANTIEPILEPTIC

Valproate

Tiagabine

ANTIPSYCHOTIC

Olanzapine

Quetiapine

PROPANOLOL

Improves physical symptoms

  • tachycardia
  • tremor

BUSPIRONE

5HT1A Agonist

Fewer side-effects (less than sedation)

Slow onset of action (days/weeks)

27
Q

Benzodiazepines are used to treat ‘panic attacks’ and other anxiety states. By what mechanism do they produce their anti-anxiety effects?

A

Enhancement of the action of GABA at GABAA receptors

28
Q

Which of the following drugs is commonly used in the treatment of insomnia?

A: Thiopental

B: Phenytoin

C: Baclofen

D: Sodium valproate

E: Temazepam

A

Temazepam

29
Q

What type of neurones release GABA?

A

Short-axon interneurons

They have regulatory/inhibitory roles

GABA = most important inhibitory neurotransmitter in the brain

30
Q

What is the GABA shunt?

A

TCA cycle forms glutamate which is used to produce GABA

Succinic acid from the metabolism of GABA is then fed back into the TCA cycle

31
Q

Why are sedatives and hypnotics grouped together?

A

They same drugs are used as sedatives and hypnotics, just the dosage is changed

Yr 2 LCRS - Pharm (44 decks)

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