Anxiolytics and Hypnotics Flashcards
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- GABA is the most important inhibitory NT in the brain
- Glial cells envelope the synapse and surround them
- One of the functions of glial cells is to ‘mop up’ NTs
What is GABA made from?
GABA is synthesised from glutamate (precursor for GABA)
Strangely, glutamate is the single most important excitatory NT in the brain
It is acted on by GAD (glutamate decarboxylase): glutamate -> GABA.
What does GABA bind to on post-synaptic neurones and what does this do?
- GABA-A receptors
- They are chloride ionophores
- They are ion channel linked (chloride channel)
- When stimulated by GABA, the ion channel changes conformation to transiently become a chloride ion
- 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
Where is GABA-B found and what is its role?
What type of receptor are they?
GABA-B receptors exist on the pre-synaptic terminals – these are type II receptors (G-protein coupled). They have a regulatory effect.
How does re-uptake of GABA occur?
- GABA must first be taken up by the surround glial cells OR back into the pre-synaptic terminal
- This reduces the synaptic concentration of GABA, but also allows for GABA metabolism
How is GABA metabolised?
- GABA transaminase (GABA-T) is the first enzyme in metabolism (GABA -> succinic semialdehyde)
- The second enzyme is succinic semialdehyde dehydrogenase (SSDH) to produce succinic acid
- Succinic acid goes back into the TCA cycle in the cells
- Glutamate also arises from the TCA cycle – this forms a GABA shunt
- Around 10% of the activity of the TCA cycle is involved in generating GABA as a transmitter
Give examples of anti-convulsant/anti-epileptic drugs, what do they inhibit?
SODIUM VALPROATE (EPILIM): GABA -T and SSDH inhibitor + Na blocker
VIGABATRIN (SABRIL): GABA -T inhibitor
Where are GABA-T and SSDH found?
both mitochondrial enzymes
How can GABA be used to cause an anti-convulsant/anti-epileptic effect?
- If we inhibit GABA metabolism, we can produce large increases in brain GABA levels
- This enhances the release of GABA in the CNS -> anticonvulsant/anti-epileptic effects
What are the 4 main proteins making up the GABA-A receptor?
- GABA receptor protein
- Benzodiazepine receptor protein
- Barbiturate receptor protein
- Chloride channel protein
What happens to the GABA-A receptor when GABA binds?
- 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
- The result is a momentary opening of the chloride channel protein -> hyperpolarisation
What is a competitive antagonist for the GABA-A receptor?
Bicuculline - competes with GABA to bind to the GABA receptor protein
What do benzodiazepines bind to and what does this do (2 effects)?
- Benzodiazepine binds to the benzodiazepine receptor protein
This has two main effects on GABA neurotransmission:
- Facilitate GABA mediated opening of the Cl- channel
- Facilitate GABA binding to its own receptor (this is reciprocated)
I.e. in the presence of GABA binding we get a facilitation of benzodiazepine binding
What is Flumezanil?
- Competitive benzodiazepine antagonist
- It competes with benzodiazepine for its binding site
What do barbiturates bind to?
What 3 effects does this have?
- Barbiturates binds to the barbiturate receptor protein
This has three main effects on GABA neurotransmission:
- Facilitate GABA mediated opening of the Cl- channel
- Facilitate GABA binding to its receptor but this is not reciprocated
At higher concentrations, barbiturates can have a direct action on the chloride channel
Can barbiturates and benzodiazepines work alone on the GABA receptor?
- Benzodiazepines and barbiturates have no activity alone (allosteric action)
- If you take GABA out of the equation then these drugs have no activity on their own
- They are working to enhance the action of GABA, they are not direct GABA agonists by themselves
- They bind to GABA-A receptor but also bind to their own binding sites (not GABA receptor protein)
How do barbiturates and benzodiazepines work?
Barbiturates and benzodiazepines have slightly different mechanisms:
- Benzodiazepines: increase the frequency of chloride channel opening
- Barbiturates: increase the duration of the chloride channel opening
- Barbiturates also reduce excitatory transmission (some antagonist action at glutamate receptors)
- This contributes to their anxiolytic and hypnotic effects
- Barbiturates also have other membrane effects (e.g. direct action on Cl channel at higher concentrations)
Compare the selectivity of barbiturates and benzodiazepines and what this means
- Barbiturates are less selective than benzodiazepines
This reduced selectivity may explain:
- Induction of surgical anaesthesia (we can’t do that with benzodiazepines)
- Barbiturates are less safe than the benzodiazepines
What are the clinical uses of barbiturates and benzodiazepines?
- Anaesthetics (barbiturates only: thiopentone)
- Anticonvulsants – barbiturates (diazepam, clonazepam) and barbiturates (phenobarbital)
- Anti-spastics (diazepam) – action in spinal cord and reduces AP propagation in alpha motor neurones
- Anxiolytics
- Sedatives/hypnotics
What are anxiolytics, sedatives and hypnotics?
ANXIOLYTICS: Remove anxiety without impairing mental or physical activity (“minor tranquillisers”)
SEDATIVES: Reduce mental and physical activity without producing loss of consciousness
HYPNOTICS: Induce sleep
What must anxiolytics, sedatives and hypnotics ideally do/not do?
- Have wide margin of safety
- Not depress respiration
- Produce natural sleep (hypnotics)
- Not interact with other drugs
- Not produce ‘hangovers’
- Not produce dependence
Structure of barbiturates
- Barbiturates all have a six-membered ring in the middle – they differ in their substituent groups
- It has four carbons and two nitrogens (different barbiturates have different groups at specific sites)
Give an examples of a barbiturate and its use
AMOBARBITAL: useful in severe intractable insomnia, t½ 20-25 hours
**Barbiturates were once our front line sedative/hypnotic drugs – but they have many unwanted effects
What are the unwanted effects of barbiturates?
- They possess low safety margins (depress respiration -? overdosing lethal)
- Alter natural sleep (decrease REM sleep) -> hangovers and irritability
- Enzyme inducers – barbiturates induce microsomal enzymes – so avoid co-administration
- Potentiate effect of other CNS depressants (e.g. Alcohol)
- Tolerance
- Dependence: withdrawal syndrome: insomnia, anxiety, tremor, convulsion and death
Give examples of benzodiazepines
DIAZEPAM, OXAZEPAM, TEMAZEPAM
Structure of benzodiazepines and what do they all act on? Compare potencies and mechanism of action
- The structure is tricyclic: classic three-ring structure (2 six-membered and 1 seven-membered)
- There are around 20 available – but they all act at GABAA receptors
- They all have similar potencies & profiles, and have the same mechanism
- Pharmacokinetics of different types largely determine use
How are benzodiazepines:
- administered?
- distributed?
- metabolised?
- excreted?
- duration of action?
Administration
- Well absorbed orally
- Peak plasma concentration is reached after about 1 hour
- Sometimes IV – used in the treatment of status epilepticus (continuous seizure activity)
Distribution
- Bind plasma proteins strongly
- Highly lipid soluble - large volume of distribution in the body
Metabolism
- Usually extensively metabolised in the liver
Excretion
- Excreted in the urine as glucuronide conjugates
Duration of Action
- Varies a lot
- This allows classification of the drugs as short-acting or long-acting
- Long-acting either has slower metabolism or generates active metabolites
Which benzodiazepines are short/long acting?
Short-Acting: OXAZEPAM and TEMAZEPAM
Long-Acting: DIAZEPAM
How are oxazepam, temazepam and diazepam metabolised?
OXAZEPAM:
- Metabolised in the liver to its inactive glucuronide
TEMAZEPAM:
- Metabolised initially to oxazepam, which is then converted to the glucuronide conjugate
DIAZEPAM:
- Metabolised via temazepam and oxazepam to the glucuronide
**Some diazepam is metabolised through nordiazepam then oxazepam. So diazepam has slower metabolism than the other two and it also generates active metabolites
Benzodiazepines as anxiolytics - which can be used and why?
What happens in hepatic impairment, which drug is used and why?
- Benzodiazepines can be used as anxiolytics and sedative/hypnotics
- Anxiolytics (generally the longer acting benzodiazepines)
- DIAZEPAM – classic anxiolytic benzodiazepine
- CHLORDIAZEPOXIDE (librium)
- NITRAZEPAM
If the patient has hepatic impairment then the metabolism of the drug will be slowed so in this case you can use a shorter-acting benzodiazepine for its anxiolytic activity - the drug of choice is OXAZEPAM (t1/2 = 8 hours).
Benzodiazepines as sedatives/hypnotics
Which are used, give examples and why?
What is an exception that can be used?
- Sedative/Hypnotics (generally the shorter acting benzodiazepines)
- TEMAZEPAM
- OXAZEPAM
- Exception: NITRAZEPAM (t1/2 = 28 hours) – can be used as a sedative/hypnotic (it also has a daytime anxiolytic effect)
What are the advantages of benzodiazepines?
- Benzodiazepines have largely superseded the barbiturates
- They have a wider margin of safety – overdose -> prolonged sleep (this is rousable)
- We can give an intravenous shot of flumazenil (competitive antagonist) to overcome this
- Mild effect on REM sleep -> so do not induce the hangover effect
- Do not induce liver enzymes
What are the unwanted effects of benzodiazepines?
- Sedation – when they are being used as anxiolytics the patients will feel a little drowsy
- Confusion, ataxia (impaired manual skills)
- Potentiate other CNS depressants (e.g. alcohol and barbiturates)
- Tolerance (but less than barbiturates because of tissue tolerance only - no pharmacokinetic tolerance)
- Dependence
Associated with withdrawal syndrome (but less than barbiturates)
Drugs should be withdrawn slowly - Free plasma concentration of benzodiazepines can be increased by giving aspirin and heparin –
They are plasma protein bound and compete with benzodiazepines
What is zopiclone?
- Short acting (t½ is around 5 hours)
- Acts at benzodiazepine receptor but it is NOT a benzodiazepine
- It does enhance GABA-mediated neurotransmission by binding to the BZ binding site
- But it is actually a cyclopyrrolone (not a benzodiazepine)
- Sedative/hypnotic
- Similar efficacy to benzodiazepines
- Minimal hangover effects
- Minimal hangover effects but dependency still a problem
Give examples of anxiolytics
- Some anti-depressants: SSRIs
Less sedation & dependence/delayed response/long-term treatment - Some anti-epileptic drugs: Valproate, tiagabine
- Some antipsychotic drugs:
Olanzapine, quetiapine - Propranolol
This is a non-selective beta-blocker
It improves the physical symptoms of anxiety
E.g. Tachycardia (b1) and Tremor (b2) - Buspirone
5-HT1A agonist
Has fewer side-effects (less sedation compared to benzodiazepines)
Downside: slow onset of action
