Anxiolytics and Hypnotics Flashcards by Georgia Leggett

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

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

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

GABA modulin

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Describe the normal physiological action of GABA.

GABA binds to the GABA receptor protein
GABA modulin links the GABA receptor protein + benzodiazepine receptor protein
Results in opening of the chloride ion channel, causing hyper polarisation of the cell

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Name a competitive antagonist of the GABA A receptor protein.

Biciculline

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Name a competitive antagonist of the benzodiazepine receptor protein. When is this used therapeutically?

Flumazenil

Used to treat Benzodiazepine OD

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

Facilitate GABA-mediated opening of cl- channel

Increase affinity of GABA to the GABA binding site– reciprocated with enhanced BZ binding

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

Enhance normal physiological action of GABA
Enhance GABA binding to the GABA receptor protein (NOT reciprocated)
At higher concs, BARBs can directly open Cl- channel

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

Benzodiazepines: increase frequency of cl- channel opening
Barbiturates: increase duration of cl- channel opening

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

Barbiturates are LESS selective
May explain why barbiturates induce surgical anaesthesia + are less safe than benzodiazepines
Barbiturates also reduce excitatory transmission

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Name a barbiturate that is used as an anaesthetic.

Thiopentone

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Name 3 barbiturates and benzodiazepines that are used as anti-convulsants.

Diazepam
Clonazepam
Phenobarbital

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

Diazepam

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What are two other clinical uses of benzodiazepines and barbiturates?

Anxiolytics

Sedatives/ Hypnotics

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Define anxiolytic.

Remove anxiety without impairing mental or physical activity

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Define sedative.

Reduce mental + physical activity without producing loss of consciousness

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Define hypnotic.

Induces sleep

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What structure is common to all barbiturates?

6-membered ring (4 carbons + 2 nitrogens)

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Barbiturates have been largely superseded by benzodiazepines. Which barbiturate is still used relatively commonly? What is it used for? What is the half-life of this drug?

Amobarbital
Severe intractable insomnia
20-25 hours

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What are 6 unwanted effects of barbiturates?

Low safety margin (depresses respiration, OD = lethal)
Alters natural sleep (reduced REM, causes hangovers)
Enzyme inducers (cause faster metabolism of other drugs + thus decreases their efficacy)
Potentiates action of other CNS depressants (e.g. alcohol)
Tolerance (Tissue + pharmacokinetic)
Dependence (withdrawal syndrome results)

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What structure is common to all benzodiazepines?

They are tricyclic

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What are the three key benzodiazepines?

Diazepam
Oxazepam
Temazepam

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

Their pharmacokinetics

Describe the administration of benzodiazepines.

Well absorbed per orally

Peak plasma concentration after ~ 1 hour

When would you give IV benzodiazepines?

Treatment of status epilepticus

Describe the distribution of benzodiazepines.

Bind strongly to plasma proteins | Highly lipid soluble, results in wide distribution

Describe the metabolism of benzodiazepines.

Extensively metabolised in the liver

Describe the excretion of benzodiazepines.

Excreted in the urine as glucuronide conjugates

Describe the duration of action of benzodiazepines.

Varies a lot | Allows classification as short- + long-acting

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

Have slower metabolism | Generate active metabolites

Name two short-acting benzodiazepines.

Oxazepam | Temazepam

Name a long-acting benzodiazepine.

Diazepam

Describe the metabolism of oxazepam.

Metabolised straight to its glucuronide conjugate (t1/2 = 8 hours)

Describe the metabolism of temazepam.

Metabolised to oxazepam, then to the glucuronide conjugate

Describe the metabolism of diazepam.

Metabolised via temazepam + oxazepam to the glucuronide conjugate Some diazepam is metabolised to nordiazepam + then oxazepam

Name three drugs that are used as anxiolytics.

General rule: long-acting benzodiazepines Diazepam Chlordiazepoxide Nitrazepam

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

Hepatic impairment: means BZs are metabolised more slowly | Use oxazepam

Name two drugs that are used as sedatives/hypnotics.

General rule: short-acting benzodiazepines Oxazepam Temazepam

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

Nitrazepam (t1/2 = 28 hours) | If waking early or anxiolytic effect desired in day

What are 5 advantages of benzodiazepines over barbiturates?

Wide margin of safety OD causes prolonged sleep (but is rousable) Flumezanil can be given IV if a patient has OD Mild effect on REM sleep Do NOT enhance liver enzymes

What are 7 unwanted effects of benzodiazepines?

Sedation Confusion Ataxia Potentiate other CNS depressants (e.g. alcohol) Tolerance (tissue only) Dependence (less intense withdrawal syndrome than BARBs) Free plasma conc. can be increased by giving aspirin + heparin

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

Zopiclone: a cyclopyrrolone + it’s short-acting (t1/2 = 5 hours) acts on BZ receptor but not a BZ Has fewer hangover effects but dependency is still an issue

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

Propranolol Tachycardia Tremor

Name a new drug that has started being used as an anxiolytic. What are its advantages and disadvantages?

Buspirone: 5HT1A agonist Relatively few side effects + causes less sedation than BZs Downside: slow onset of action (max. anxiolytic effects not seen for days/weeks)

What is the precursor molecule to GABA? What enzyme causes the conversion to GABA?

Glutamate | Glutamate decarboxylase GAD

What are GABA-B receptors?

GABA auto receptors on presynaptic nerve terminals | Regulate GABA release into synapse

What type of GABA receptor is found on the post-synaptic membrane?

GABA-A receptors

Describe the metabolism of GABA. What type of enzymes mediate this?

GABA reuptake into pre-synaptic or glial cells GABA-T converts GABA to Succinic semialdehyde SSDH converts this to Succinic acid Mitochondrial enzymes

What happens if metabolism of GABA is inhibited?

Increased inhibition of the brain | Used in treatment of epilepsy

Why are barbiturates and benzodiazepines referred to as positive allosteric modulators?

Without GABA they have no action | They enhance action of GABA at GABA receptor

What other classes of drugs can be used as anxiolytics?

``` Some antidepressants e.g. SSRIs Some antiepileptcs e.g. Valproate Some antipsychotics e.g. Quetiapine Propanolol Busiprone ```