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 trasnient 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 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
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
Name a barbiturate that is used as an anaesthetic.
Thiopentone
Name three barbiturates and benzodiazepines that are used as anti-convulsants.
Diazepam (BDZ)
Clonazepam (BDZ)
Phenobarbital (BARB)
Name a benzodiazepine that is used as an anti-spastic.
Diazepam
What are the clinical uses of benzodiazepines and barbiturates?
Anaesthetics (BARBs only) Anticonvulsants Anti-spastics Anxiolytics Sedatives/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)
Differ in R1 R2 and X substituants
Barbiturates have been largely superseded by benzodiazepines. Which barbiturate is still used relatively commonly and what for?
Amobarbital
As a sedative/hypnotic
Induces severe intractable insomnia
Usually only if patient isn’t responding to benzodiazepines
What is the half-life of Amobarbital?
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 (tissue and pharmacokinetic)
Dependence
What structure is common to all benzodiazepines?
They have a three ring structure (tricyclic)
Differ in their 4 substituant groups
Relativley small changes in all the groups
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 (tonic clonic seizure lasting more than 30 minutes - medical emergency)
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 with their half lives.
Oxazepam
Temazepam
(t1/2 = 8 hours)
Name a long-acting benzodiazepine and its glaf life.
Diazepam
t1/2 = 32 hours
Describe the metabolism of oxazepam.
It is metabolised straight to its glucuronide conjugate
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
Note:
nordiazepam has some Benzodiazepine activity
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. Why would it be used?
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
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
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
How does zopiclone work?
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
What drug is used to control the physical symptoms of anxiety?
Propranolol
Beta blocker that prevents:
TACHYCARDIA (beta1)
TREMOR (beta2)
Name a new drug that has started being used as an anxiolytic.
Buspirone – 5HT1A agonist
Describe the morphology of GABA neurones.
They are generally short inhibitory interneurons
Where do you find longer GABA tracts?
Striato-nigral (Striatum to substantia nigra)
Cerebellar
What is the main action of GABA neurones?
Widespread inhibitory action in the CNS
How is GABA synthesised?
Glutamate is converted to GABA by GABA decarboxylase
What does GABA decarboxylase need for optimal activity?
Vitamin B6
What does GABA act on?
Stimulates the GABAa receptor - a type 1 receptor cholride ionophore
Often found on Glutaminergic, dopaminergic and 5HT neurones
What is glutamate?
An amino acid
Single most excitatory neurotransmitter in the brain
How is GABA neutralized?
Primarily by re-uptake into glial cells or presynaptic terminal
Metabolised by GABA-T (GABA transaminase) to SSA (Succinic semialdehyde)
What is the function of the GABAb receptor?
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
Where is GAD found?
This enzyme is exclusive to GABA nerve terminals – it is a marker for GABA neurones
How is GABA released from the presynaptic terminal?
Calcium-mediated exocytosis in vesicles
How is GABA metabolised?
GABA converted to Succinic semialdehyde by GABA transaminase (GABA-T)
Succinic semialdehyde converted to succinic acid by succinic semialdehyde dehydrogenase (SSDH)
Where are the enzymes of GABA metabolism found?
Mitochondrial membrane
What is the GABA shunt?
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
Where is GAD found in the cell?
In the cytoplasm
What are 2 drugs that inhibit GABA metabolism?
Sodium Valproate - covalently binds to GABA-T a ‘Suicide inhibitor’
Valproate - inhibits both GABA-T and SSDH. Also possibly reduced glutmate release from neurones
What is flumazenil used for?
Reversal of benzodiazepine overdose
It has affinity but no efficacy for the BDZ receptor as acts as a competitive inhibitor
Other than their action at the GABAa receptor, what other actions do Barbiturates have?
Reduce the activity of glutamate receptors, therefore reduce excitatory transmittion
What is meant by allosteric?
Barbiturates and benzodiazepines bind to a different site than GABA on the same receptor
What is the difference between a sedative and a hypnotic?
The same drugs are used
Hypnotics are just at higher doses of the drug
Why is phenobarbital not sued much anymore?
It has many side effects
What does Diszepam have its action on?
Alpha motor neurones in the spinal cord - caused muscle relaxation
Why is thiopentone used as an aneasthetic?
It has a very rapid action as it is very lipid soluble
What’s the class and half life of zopiclone?
cyclopyrrolone
It’s short-acting (t1/2 = 5 hours)
What are the positive and negative effects of zopicone?
Positive:
Minimal hangover effects
Negative:
Dependency still an issue
What are the positive and negative effects of buspirone?
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)
