26: Anxiolytics, Sedativs and Hypnotics Flashcards
Explain the Synthesis of GABA
Glutamate –Glutamate decarboxylase (GAD) –> GABA
Explain the effects of GABA on the postsynaptic memrane
- Binds to GABA(A) receptors causing
- hyperpolerisation via Cl- influx
How is GABA in the synaptic cleft inhibited?
Via reupttake
- into presynaptic cell
- into ajacent Glial cells
What are the targets of GABA once it is in the synaptic cleft?
- Postsynaptic GABAA receptors
- Autorecepors on presynaptic membrane
- negative feedback to reduce GABA release
Explain the Metabolism of GABA
Happens in Mitochondria after uptake
- Either directly recycled into vesicles
- or: GABA– GABA Transaminase (GABA T) –> Succinic Semialdehyde — Succinic Semialdehyde dehydrogenase –> Succinig acid (goes back to TCA cycle)
What happens when you inhibit GABA metabolism?
When is this therapeutically useful?
- leads to large increase in GABA and GABA release
- used as Anti-convulsants (e.g. sodium valporate)
Explain the structure of a GABA A receptor compex
- There are 4 (5) Subunits
- GABA receptor protein
- if GABA is bound linked by GABA modulin to:
- Benzodiazepine receptor protein
- Barbiturate receptor protein
- All three surround: Chloride Channel protein
- GABA receptor protein
Where does GABA on the GABAA receptor complex bind to?
What happens/changes with binding?
- GABA binds to GABA receptor protein
- causes GABA modulin to link GABA receptor protein linking with Benzodiazepine receptor protein
- Causes Cl- channel opening
- Also enhances binding of Benzodiazepines
Explain the MOA of Benzodiazepines
- Bind to Benzodiazepine Receptor protein on GABA receptor unit
- enhances effect of GABA on receptor
- cause increased GABA binding (bidirectional) leading to
- Increased frequency of Cl- channel binding
What is a PAM?
Positive allosteric modulator
- drugs that enhance the binding protein at the receptor (bind to different target site)
- In example of GABA receptors: Benzodiazepines and Barbiturates
Explain the MAO of Barbiturates
- Bind to the Barbiturate Receptor protein of the GABA receptor unit causing
- enhanced normal action of GABA (unidirectional)
- at high doses: direct stimmulaiton and opening of Cl- channels causing
- increased duration of Cl- channel opening
- Also: decrease Glutamate mediated exitation (less selective than Bz)
Explain why Barbiturates have a lower margin of safety but can also be used to induce anesthesia?
They are less selective than Benzodiazepines
- reduce exitory transmission (Glutamate mediated)
- have also more membrane effects
What are the clinical uses of Barbituates?
- Induction of Anesthetic e.g. Thiopentone
- Anticonvulsants
- Sedative/Hypnotic effects (e.g. Amobarbital in severe insomnia (with t1/2 20-25 h)
What are the clinical uses of Benzodiazepines?
- Anticonvulsants (e.g. Diazepam, Clonazepam)
- Anti-spastics
- Anxiolytic (long acting)
- Sedative/Hypnotics (short acting)
What is an anxiolytic?
Remove Anxiety wihout impairing mental or physical activity
What is an sedative?
What is an Hypnotic?
What is their difference?
- Sedative= reduce mental and pyhsical activity without producing loss of consciousness
- Hypnotics= induce sleep
- Difference: often only the dose is different not the drug
What are the side effects of the use of Barbiturates?
Many side effects: not first choice of treatment
- Respiratory depressive
- low safety margin
- overdose it lethal
- Alter natural sleep pattern (reduction in REM) –> Hangovers
- Enzyme inducer
- Potentiate effects of other CNS depressants (e.g. Alcohol)
- Tolerance development (tissue and pharmacokinetic)
- Dependance with severe withdrawl symptoms
- insomnia
- anxiety
- tremor
- convulsants
- death
What are the differences between the different benzodiazepines available?
Normally: all same/similar structure but different pharmakokinetic properties (all same target+ similar potencies)
Summarise the pharmacokinetics of Benzodiazepines
- Administration
- PO (after 1h effects)
- IV as anti-convulsant treatment in status epilepticus
- Distibution
- heavily Plasma Protien bound
- soluble –> wide distribution
- Metabolism (extensive in the liver) –> forms glucuronite conjugates
- Excretion in urine
Name an example of a long acting Benzodiazepine
What is its use?
How is it metabolised?
E.g. Diazepam (t1/2 32h)
- normally used as anxiolytic
- metabolised via forming active metabolies (of short acting Benzodiazepines)
- Exception: Oxacepam in liver impairment –> bcomes long-acting due to slow metabolism
Which Benzodiazepines can be used as an Anxiolytic?
Long Acting (e.g. Diazpam)
- exeption: Oxazepam in liver damage might get metabolised slower –> made long acting
Name short acting benzodiazepines and summarist their use and metabolism
Metabolised and form Glucuronide conjugates
- E.g. Temazepam, Oxazepam (t1/2 8h)
- used as sedatives/hypnotics
- Exeption: NITRAZEPAM long acting but can be used to treat insomia + have daytime anyiolytic effects
What are the advantages of the use of Benzodiazepine over Barbiturates?
- wide margin of safety
- overdose caues prolonged but rousable sleep
- Antagonist Available (Flumazenill)
- only mild effect on REM sleep
- no enzyme inducers
What are the side-effects of Benzodiazepines?
- Sedation, Confusion, amnesia, ataxia (–> should not drive)
- Potentiation of other neurodepressants
- Tolerance (but less than Barbs –> only tissue)
- Dependance (similar to Barbs but less intense)
- slow withdraw aimed
- Can be displaced from PP by other PP binding drugs
