Anxiolytics and Hypnotics Flashcards
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
What protein links the GABA receptor proteins and the benzodiazepine receptor protein?
GABA modulin
Describe the normal physiological action of GABA.
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
Name a competitive antagonist of the GABA receptor protein.
Biciculline
Name a competitive antagonist of the benzodiazepine receptor protein.
Flumazenil
What are the two main effects of benzodiazepines that facilitate GABA neurotransmission?
They facilitate the GABA-mediated opening of the chloride channel
They facilitate the binding of GABA to its receptor protein (increase theaffinity of GABA to the GABA binding site) – this is reciprocated
What are the three main effects of barbiturates that facilitate GABA neurotransmission?
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
What is the key difference in the mechanism of action of barbiturates and benzodiazepines?
Benzodiazepines – increase the frequency of chloride channel opening
Barbiturates – increase the duration of chloride channel opening
What is the relative difference in selectivity between barbiturates and benzodiazepines?
Barbiturates are LESS selective
This may explain why barbiturates induce surgical anaesthesia and why barbiturates are less safe than benzodiazepines
NOTE: barbiturates also reduce excitatory transmission
Name a barbiturate that is used as an anaesthetic.
Thiopentone
Name three barbiturates and benzodiazepines that are used as anti-convulsants.
Diazepam
Clonazepam
Phenobarbital
Name a benzodiazepine that is used as an anti-spastic.
Diazepam
What are two other clinical uses of benzodiazepines and barbiturates?
Anxiolytics
Hypnotics
Define anxiolytic.
Remove anxiety without impairing mental or physical activity
Define sedative.
Reduce mental and physical activity without producing loss of consciousness
Define hypnotic.
Induces sleep
What structure is common to all barbiturates?
Six-membered ring (4 carbons and 2 nitrogens)
Barbiturates have been largely superseded by benzodiazepines. Which barbiturate is still used relatively commonly?
Amobarbital
What is the half-life of this drug?
20-25 hours
What are the unwanted effects of barbiturates?
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
Dependence
What structure is common to all benzodiazepines?
They are tricyclic
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 about 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
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
This allows classification as short-acting and long-acting benzodiazepines
What makes long-acting benzodiazepines have a long duration of action?
They have slower metabolism
They generate active metabolites
Name two short-acting benzodiazepines.
Oxazepam
Temazepam
Name a long-acting benzodiazepine.
Diazepam
Describe the metabolism of oxazepam.
It is metabolised straight to its glucuronide conjugate (t1/2 = 8 hours)
Describe the metabolism of temazepam.
Metabolised to oxazepam and then to the glucuronide conjugate
Describe the metabolism of diazepam.
Metabolised via temazepam and oxazepam to the glucuronide conjugate
Some diazepam is metabolised to nordiazepam and 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 – this means that the benzodiazepines and metabolised more slowly – drug of choice = 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.
Nitrazepam (t1/2 = 28 hours)
What are the advantages of benzodiazepines over barbiturates?
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
What are the unwanted effects of benzodiazepines?
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
Name a sedative/hypnotic that isn’t a benzodiazepine. What class of drug does this fall into?
Zopiclone – this is a cyclopyrrolone and it’s short-acting (t1/2 = 5 hours)
NOTE: it acts on the benzodiazepine receptor but it is not a benzodiazepine
This has fewer hangover effects but dependency is still an issue
What drug is used to control the physical symptoms of anxiety?
Propranolol
Name a new drug that has started being used as an anxiolytic.
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)
