25. Anxiolytic, Sedative and Hypnotic Drugs Flashcards
What is the most important inhibitory NT in the brain?
GABA
What envelopes the GABAergic synapse?
Glial cells
What is GABA synthesised from?
- Glutamate (most important excitatory NT in the brain)
* GAD (glutamate decarboxylase) converts glutamate => GABA
What does GABA do when it is released into the synaptic cleft and how does it affect transmission activity?
- Diffuses towards the post-synaptic receptors (GABA-A receptors - type I) = chloride ionophores
- Stimulation causes ion channel conformation change
- Chloride flows through - it’s negative so it hyperpolarises the post-synaptic cell
- This negative potential makes it harder to excite neurones
How is GAVA removed from the synaptic cleft?
- Taken up by glial cells
- Taken back up into the pre-synaptic terminal
- Reduces synaptic concentration and allows for metabolism
What do GABA-B receptors do?
- Exist on the pre-synaptic terminals
- Type II - G-protein coupled
- Regulatory effect (auto-receptors)
- When [GABA] is high in synaptic cleft, less GABA is released
Describe the metabolism of GABA?
1) GABA transaminase: GABA => succinic semialdehyde
2) Succinic semialdehyde dehydrogenase (SSDH) turns it into succinic acid
3) Succinic acid goes into the TCA cycle
(glutamate also arises from the TCA cycle)
Where are the enzymes GABA-T and SSDH found?
Mitochondria
What happens if we inhibit GABA metabolism and why is this useful?
- Enhances release of GABA in CNS
* Anticonvulsant/anti-epileptic effects
Give examples of drugs that inhibit GABA metabolism and how they do it?
- Sodium valproate (epilim) - GABA-T and SSDH inhibitor + Na blocker (reduces some glutamate release)
- Vigabatrin (sabril) - GABA-T inhibitor
Describe the structure of the GABAA receptor complex
Four main proteins • GABA receptor protein • Benzodiazepine receptor protein • Barbiturate receptor protein • Chloride channel protein
What happens to GABAA when GABA binds?
- GABA receptor protein and benzodiazepine receptor protein link together
- Mediated by peptide: GABA modulin (which links with the GABA + benzodiazepine receptor proteins)
- Results in momentary opening of chloride channel protein => hyperpolarisation
What is Bicuculline?
- Competitive antagonist for the GABAA receptor
- Competes with GABA for the binding site on the GABA receptor protein
- The compound mimics the epilepsy, as it blocks the inhibitory actions of GABA
How do benzodiazepines work?
Bind to the benzodiazepine receptor protein
1) Facilitates GABA mediated opening of the Cl- channel
2) Facilitates GABA binding to its own receptor - reciprocal as this facilitates benzodiazepine binding
Increases inhibitory effect of GABA on GABAA
What is flumezanil?
- Competitive benzodiazepine antagonist (antidote)
- Same tricyclic structure as agonist
- Binds to benzodiazepine receptor but has no efficacy
How do barbiturates work?
Bind to the barbiturate receptor protein
1) Facilitates GABA mediated opening of the Cl- channel
2) Facilitates GABA binding to its receptor (not reciprocated)
3) Direct action on chloride channels at higher concentrations
Increases inhibitory effect of GABA on GABAA
Do benzodiazepines and barbiturates have activity alone (work without GABA involved)?
- No
- However, barbiturates do at higher concentrations e.g. direct action on Cl- channel
- Allosteric action
- Other binding sites apart from GABAA
How are barbiturates different to benzodiazepines in their effect?
- Barbiturates increase the duration of chloride channel opening, rather than frequency
- Less selective
- Reduce excitatory transmission (antagonist action at glutamate receptors)
- Other membrane effects e.g. direct Cl- channel action
Which GABAA agonist is used for surgical anaesthesia and which is safer?
- Barbiturates used for induction of surgical anaesthesia
- Barbiturates are also less safe
(due to reduced selectivity)
What are the clinical uses of benzodiazepines e.g. diazepam?
- Anticonvulsants
- Anti-spastics
- Anxiolytics
- Sedatives
- Hypnotics
What are the clinical uses for barbiturates?
- Anaesthetics
- Anticonvulsants
- Anxiolytics
- Sedatives
- Hypnotics
What are anxiolytics, sedatives and hypnotics?
- Anxiolytics - remove anxiety without impairing mental or physical activity
- Sedatives - reduces mental and physical activity without producing loss of consciousness
- Hypnotics - induce sleep
Describe the structure of barbiturates
- Six-membered ring in the middle
* 4 carbons and 2 nitrogens
What is amobarbital used for and what is it’s half life?
- Severe intractable insomnia
* Half-life: 20-25 hours
What are the unwanted effects of barbiturates?
- Low safety margins - depress respiration
- Alter natural sleep - decrease REM sleep
- Induce microsomal enzymes - avoid co-administration
- Potentiate effects of CNS depressants
- Tolerance - tissue and pharmacokinetic
- Dependence - withdrawal syndrome: insomnia, anxiety, tremor, convulsion, death
Describe the structure of benzodiazepines and how do different types differ
- Tricyclic
- 20 available, but all have similar potencies + profiles and the same mechanisms (pharmacodynamics)
- Pharmacokinetics of different types largely determine use
Describe the absorption and peak plasma concentration of benzodiazepines
• Well absorbed orally
(• Sometimes given IV to treat status epilepticus)
• Peak plasma concentration after 1 hour
Do benzodiazepines bind to plasma proteins strongly and how lipid soluble are they?
- Bind plasma proteins strongly
* Highly lipid soluble
Where are benzodiazepines metabolised and excreted?
- Metabolised in the liver
* Excreted in the urine as glucuronide conjugates
Describe the duration of action of benzodiazepines
- Varies
- Short (e.g. oxazepam t1/2 = 8 hours) or long-acting (e.g. diazepam t1/2 = 32 hours)
- Long-acting has a slower metabolism or generates active metabolites
What is oxazepam, temazepam and diazepam metabolised to?
- Oxazepam => inactive glucuronide
- Temazepam => oxazepam => inactive glucuronide
- Diazepam => temazepam / nordiazepam => oxazepam => inative glucuronide
Are anxiolytics generally shorter or longer acting than benzodiazepines, and give examples?
Generally longer acting
• Diazepam
• Chlordiazepoxide
• Nitrazepam
What are the unwanted effects of benzodiazepines?
- Sedation
- Confusion, ataxia
- Potentiate other CNS depressants
- Tolerance (tissue not pharmacokinetic
- Dependence
- Free plasma conc. can be increased by giving aspirin etc.
What is zopiclone?
- Sedative/hypnotic
- “Z-drug”
- Cyclopyrrlone
- Acts at benzodiazepine and enhances GABA actions (but is not a benzodiazepine)
- Dependency is still a problem
Apart from the main anxiolytics, what other drugs can be used?
- Some anti-depressants - SSRIs
- Some anti-epileptic drugs
- Some antipsychotic drugs
- Propranolol (for physical symtoms)
- Busiprone - 5-HT agonist
