26. Anxiolytic, sedative and hypnotic drugs Flashcards
what is one of the functions of glial cells?
to envelope the synapse and surround GABA (the most important inhibitory NT in the brain) so that it can be ‘mopped up’
why is the precursor of GABA strange?
the precursor of GABA is glutamate which is the single most important excitatory NT in the brain
it is acted on by glutamate decarboxylase –> GABA
what is the difference between GABA-A and GABA-B receptors?
GABA-A receptors sit on the post-synaptic membranes and are chloride ionophores (ion channel-linked)
GABA-B receptors exist on pre-synaptic terminals and are type 2 receptors (G-protein coupled)
what happens when GABA-A receptors are stimulated by GABA?
- the ion channel changes conformation to become a chloride ion channel
- chloride is negative so they hyperpolarise the post-synaptic cell
- if the cell has a very negative potential, it is harder to excite –> this is how GABA dampens down activity
how is GABA metabolised?
- GABA transaminase converts GABA –> succinic semialdehyde
- succinic semialdehyde dehydrogenase (SSDH) converts succinic semialdehyde –> succinic acid
- succinic acid goes back into the TCA cycle in the cells
- glutamate arises from the TCA cycle which forms a GABA shunt
what can the inhibition of GABA metabolism result in?
- large increases in brain GABA levels
- this enhances the release of GABA in the CNS –> anticonvulsant/anti-epileptic effects
name 2 GABA metabolism inhibitors
- sodium valproate (epilim) is a GABA-T and SSDH inhibitor and Na blocker
- vigabatrin (sabril) is a GABA-T inhibitor
what 4 main proteins are GABA-A receptors composed of?
- GABA receptor protein
- benzodiazepine receptor protein
- barbiturate receptor protein
- chloride channel protein
what causes the opening of the chloride channel protein when the GABA-A receptor is stimulated?
- when GABA binds to the GABA-A receptor it binds to the GABA receptor protein
- when this happens, GABA receptor protein and benzodiazepine receptor protein link together
- this is mediated by a peptide called GABA modulin
- this results in a momentary opening of the chloride channel protein –> hyperpolarisation
what is bicuculline?
a competitive antagonist for the GABA-A receptor
what effects on GABA neurotransmission do benzodiazepines have?
- facilitates GABA mediated opening of the Cl- channel
- facilitates GABA binding to its own receptor (reciprocated - in the presence of GABA binding there is facilitation of benzodiazepine binding)
what is flumezanil?
competitive benzodiazepine antagonist
what effects on GABA neurotransmission do barbiturates have?
- facilitate GABA mediated opening of the Cl- channel
- facilitate GABA binding to its receptor (not reciprocated)
- at higher concentrations they have a direct action on the chloride channel
what does the ‘allosteric action’ of benzodiazepines and barbiturates mean?
they have no activity alone - they are working to enhance the action of GABA, they are not direct GABA agonists by themselves
what is the difference between benzodiazepines and barbiturates?
- benzodiazepines increase the frequency of chloride channel opening
- barbiturates increase the duration of chloride channel opening
- barbiturates are less selective than benzodiazepines
- barbiturates also reduce excitatory transmission
what are the clinical uses of benzodiazepines and barbiturates?
BARBITURATES ONLY
- anaesthetics (thiopentone)
BENZODIAZEPINES ONLY
- anti-spastics (diazepam)
BOTH
- anticonvulsants (benzodiazepines: diazepam, clonazepam and barbiturates: phenobarbital)
- anxiolytics
- sedatives/hypnotics
what do anxiolytics do?
remove anxiety without impairing mental or physical activity
what do sedatives do?
reduce mental and physical activity without producing loss of consciousness
what do hypnotics do?
induce sleep
what should anxiolytics, sedatives and hypnotics ideally do?
- have wide margins of safety
- not depress respiration
- produce natural sleep
- not interact with other drugs
- not produce ‘hangovers’
- not produce dependence
what is the general structure of barbiturate molecules?
- 6-membered ring in the middle
- differ in the substituent groups
- has 4 carbons and 2 nitrogens in the ring
what are the unwanted effects of barbiturates?
- possess low safety margins (depress respiration –> lethal if overdosed)
- alter natural sleep –> hangovers and irritability
- enzyme inducers
- potentiate effect of other CNS depressants (e.g. alcohol)
- tolerance
- dependence: withdrawal symptoms of insomnia, anxiety, tremor, convulsion and death
what is the general structure of benzodiazepine molecules?
- tricyclic: classic 3-ring structure
- around 20 available
- all have similar potencies and profiles and have the same mechanism
what are 3 key benzodiazepines?
- diazepam
- oxazepam
- temazepam
how are benzodiazepines administered?
- well absorbed orally
- peak plasma concentration is reached after an hour
- sometimes given via IV
how are benzodiazepines distributed, metabolised and excreted?
DISTRIBUTION
- bind plasma proteins strongly
- highly lipid soluble
METABOLISM
- extensively in the liver
EXCRETED
- in the urine as glucuronide conjugates
what is the duration of action of benzodiazepines?
- varied
- drugs are classified as either short-acting or long-acting
- long-active drugs have slower metabolism or generate active metabolites
give examples of short-acting benzodiazepines and how they are metabolised
OXAZEPAM: metabolised in the liver to its inactive glucuronide
TEMAZEPAM: metabolised to oxazepam –> inactive glucuronide
give an example of a long-acting benzodiazepine and how it is metbolised
DIAZEPAM: metabolised via temazepam and oxazepam to the inactive glucuronide
which benzodiazepines are used as anxiolytics?
the longer acting benzodiazepines:
- diazepam
- chlordiazepoxide
- nitrazepam
when would a shorter-acting benzodiazepine be used?
when a patient has hepatic impairment - the metabolism of the drug is slowed so a shorter-acting drug can be used (usually oxazepam)
which benzodiazepines are usually used as sedatives/hypnotics?
the shorter acting benzodiazepines:
- temazepam
- oxazepam
what are the advantages of benzodiazepines
- wider margin of safety than barbiturates - overdose –> prolonged sleep (but this is rousable)
- mild effect on REM sleep –> do not induce the hangover effect
- do not induce liver enzymes
what are the unwanted effects of benzodiazepines?
- sedation: when used as anxiolytics the patient will feel drowsy
- confusion, ataxia
- potentiate other CNS depressants
- tolerance
- dependence (associated with withdrawal symptoms)
how can free plasma concentration of benzodiazepines be increased?
by giving aspirin and heparin: they are plasma protein bound and compete with benzodiazepines
what is zopiclone?
- short acting
- acts at benzodiazepine receptor but is not a benzodiazepine
- enhances GABA-mediated neurotransmission by binding to the BZ binding site
- it is a cyclopyrrolone
- similar efficacy to benzodiazepines
- minimal hangover effects
- dependency is a slight problem
