Pharm 26 - Anxiolytic, Sedative and Hypnotic drugs Flashcards
What is the most important inhibitory neurone and what is its precursor
GABA - precursor is glutamate
GABA is an AA
How is glutamate converted into GABA?
What happens to the GABA after it is formed
GAD converts glutamate into GABA
gabs then stored in vesicles in presynaptic terminal until it is time to be exocytosed (when Ca influx)
GABA are mostly ……….. interneurons that dampen firing of …..
Short interneurons
Dampen firing of e.g. glutamate neurons
What are the 2 types of GABA receptors?
GABAa receptors - located post-synaptically and ion-channel linked; it causes Cl influx causing hyperpolarisation
GABAb receptors - these are presynaptic (auto receptors). They are self regulatory, G protein coupled (type 2)
How is GABA inactivated
- GABA reuptake (primary method) - by GABAb receptors
2. Reuptake by glial cells
Where does Glutamate come from? Where does succinate go?
TCA Cycle (GABA shunt)
GABA removed from TCA Cycle and inputted back in
The conversion of GABA to succinic acid (succinate) is 2 step. Explain this reaction
- GABA —–> Succinic semialdehyde (via GABA transaminase (GABA-T))
- Succinic semialdehyde —–> Succinic acid (via Succinic semialdehyde dehydrogenase (SSDH)).
Succinic acid then goes back into TCA
What structure are GABA-T and SSDH enzymes associated with?
They are mitochondrial enzymes
Where is GAD enzyme found and only in what type of neurones?
GAD converts glutamate to GABA
Found in cytoplasm and only in GABAnergic neurones
What happens if you inhibit GABA metabolism (i.e. by inhibiting SSDH or GABA-T)
Increase in brain GABA levels
Name 2 drugs that inhibit GABA metabolism?
These drugs are both??
- Sodium valproate (Epilim) - inhibits GABA-T and SSDH. (also acts as a VGSC blocker)
- Vigabatrin (Sabril) - selective to GABA-T (non-competitive)
Sodium valproate has more mixed action as less selective
These are both anti-convulsants
What are the 4 main proteins in the GABA receptor
- GABA receptor protein
- Benzodiazepine receptor (BDZ receptor)
- BARB receptor protein (barbiturates)
- Cl channel protein
Explain how the GABAa receptor complex works
- GABA binds to the GABAaR
- This causes GABAaR and BDZ receptor protein linkage (modulated by GABA modulin)
- This causes a transient opening of Cl- channels
Give an example of reciprocal binding in the GABAaR
If BDZ binds to the BDZ receptor - normal GABA action is enhanced (on CL- channel). Binding/affinity of GABA also enhanced.
This also works the other way - GABA binding enhances affinity of BDZ binding
Give an example of non-reciprocal binding at the GABAaR
BARB enhances GABA binding (affinity) and action at Cl channel - but this does not work the other way as with the BDZ receptor
At high doses, what can BARBs do?
Directly stimulate the Cl channel
What is bicuculline
A competitive GABAa receptor antagonist
What is flumazenil
Competitive BDZ antagonist
Benzodiazepines (BDZs) and Barbs have no activity alone because?
They are allosteric, meaning?
Because they work by enhancing GABA
Allosteric meaning they work at a site different to the GABA receptor - they are not direct GABA agonists)
What is the difference in mechanism between BARBS and BDZ
BDZ and BARBS have different binding sites and mechanisms
BDZ increases the frequency of Cl channel openings
BARBS increase the duration of Cl channel openings
Which is less selective, BARBs or BDZ?
Barbs are less selective - they decrease excitatory transmission and also have other membrane effects (at higher doses)
This may explain why they have a lower margin of safety and why they can induce surgical anaesthesia
What is a clinical usage for only Barbs and not BDZ
Anaesthesia - thiopentone is used
What are the clinical uses for BDZ and Barbs
- Anticonvulsants - diazepam, clonazepam, phenobarbital
- Anti-spastics - diazepam
- Anxiolytics
- Sedatives / hypnotics
What is the difference between anxiolytics and sedatives
Anxiolytics - remove anxiety but don’t impair mental or physical activity
Sedatives - reduce mental and physical activity without loss of consciousness
(Hypnotics - induce sleep. Same type of drugs as sedatives but different doses)
What are 6 ideal features of anxiolytics, sedatives and hypnotics?
- Wide margin of safety
- No respiratory depression
- Natural sleep
- No other drug interactions
- No hangovers
- No dependence
Barbs have what kind of structure?
Single ring structure
Give an example of a major use of barbiturates
Sedative/hypnotic - Amobarbital given for severe intractable insomnia (after 1st line BDZ given)
Amobarbital has a half life of 20-25 hrs
What are the SEs of barbs
- Low safety margins (can cause respiratory depression)
- Alters natural sleep (less REM) - causing hangovers or irritability
- Enzyme inducers
- Potentiates effect of other CNS depressants (e.g. alcohol)
- Tolerance
- Dependence, causing withdrawal symptoms (e.g. insomnia, anxiety, convulsions, etc)
Hence, Barbs are no longer first line
What is the structure of BDZ? How many BDZs are there?
3 ring structure - about 20 available
They ALL act on GABA receptors, with similar potency
Describe the administration of BDZ
- Well absorbed orally
- Peak plasma conc after 1 hr
- Given IV if status epilepticus
Describe the distribution of BDZ
BDZ binds plasma proteins very strongly
They are highly lipid soluble so have a wide distribution
How are BDZs metabolised
BDZ metabolised by liver microsomal enzymes and excreted in urine as glucuronide conjugates
BDZ can be short acting or long acting. They are long acting if?
If they have slow metabolism or they produce active metabolites
Name 4 long acting BDZ
- Diazepam (Important)
- Nordiazepam
- Nitrazepam
- Chlordiazepoxide
Name the short acting BDZs
- Temazepam (important)
- Oxazepam - important - (except if they have hepatic impairment - then slower metabolism)
- Lorazepam
What are the clinical uses of BDZs?
- Anxiolytics (long acting) - Diazepam (valium) / chlordiazepoxide / (nitrazepam)
However, if the patient has hepatic impairment, give Oxazepam instead for anxiolytic- b/c slower metabolism
- Sedative/hypnotics (short acting)- Temazepam
- Oxazepam
NB - nitrazepam can be used as BOTH a sedative and anxiolytic if you want a daytime anxiolytic effect and a night time sedative effect
What are the advantages of BDZs?
- Wide margin of safety
(OD causes prolonged sleep but can be roused)
- They do not induce liver enzymes - fewer drug interactions (unlike barbs which are enzyme inducers)
What can be given if there is a BDZ OD
Flumazenil
What are the unwanted effects of BDZ
- Sedation/confusion/amnesia/ataxia
- Potentiate other CNS depressants (e.g. alcohol, Barbs)
- Tolerance (but less than barbs and tissue only, not liver)
- Dependence causing withdrawal symptoms - not as bad as Barbs, but must withdraw slowly
- Free plasma conc can increase if other drugs e.g. aspirin/heparin present, that compete w/ plasma protein binding
Name and describe another sedative/hypnotic that is used
Zopiclone - short acting (5hrs half life) - acts at BDZ receptor and has similar efficacy to BDZ , has minimal hangover effects.
- Dependency still a problem.
Zopiclone is a cyclopyrrolone, NOT A BENZODIAZEPINE
Name and describe another anxiolytic
Certain antidepressants can be used - e.g. SSRIs
- They have less of a sedative effect may cause dependence. They also have a delayed response
- However, they are useful in the long term treatment of e.g. anxiety
Name another anti epileptic drug (anxiolytic)
Valproate, tiagibine
Name some antipsychotic drugs (anxiolytic)
Olanzapine, quetiapine
What can propranolol be used for?
It can remove some of the symptoms of anxiety - e.g. tachycardia, tremor
What is buspirone
A 5-HTA agonist, with fewer side effects (less sedation), but has a slower onset of action as an anxiolytic
