Anxiolytics and Hypnotics Flashcards
What is the difference between anxiolytics and hypnotics?
Anxiolytics are used to treat anxiety
Hypnotics treat insomnia - anxiety can cause insomnia
Describe the GABAa receptor
- Ligand gated ion channel that allows Chloride ions through when open
- causes hyperpolarisation as it brings in negative charge
- Has a pentameric structure
- 6 alpha subtypes, 3 beta, three gamma
- most common configuration is 2 alpha, 2 beta and a gamma
- Found postsynaptically
- Has multiple binding sites - GABA binds at the alpha and beta interfaces, BZDs bind to alpha/gamma interface
How is GABA taken back up?
GABA activity terminated by GABA reuptake transporter (GAT)
What does allosteric mean?
- When something binds to a site that is distinct to the agonist binding site
What are NAMs and PAMs?
Positive Allosteric Modulators either increase binding (making it easier to open) or enhance the functional response (e.g. allowing more Cl- in)
Negative Allosteric Modulators do the opposite
Give examples of PAMs
Barbiturates
BZDS
Z-drugs
What are barbiturates?
- PAMs
- bind to increase the time the channel is open - enhance functional response
- at high concentrations they are direct agonists of the GABAa receptor
What are Barbiturates still used for?
Still used in epilepsy, GA, euthanasia and capital punishment
Why have barbiturates been widely replaced by BZDs?
largely replaced by BZDs as they are cleaner, lower risk of OD and have an antidote
How do BZDs work?
- PAMs - increase binding by stabilising the GABA binding site into a configuration where it is more exposed, increasing GABA’s affinity
- Binds to the alpha/gamma interface
Why don’t BZDs bind to all GABA receptors?
- Only binds to a1,2,3,5 as they have a Histidine residue, whereas a4 and 6 have Arginine.
What is the antidote for BZD overdose?
Flumenazil - acompetetive antagonist at the BZD binding site
- Should only be a last resort as it has very bad withdrawal symptoms
Why are BZDs the most commonly used anxiolytic/hypnotic?
- They decrease anxiety AND have a sedative effect
* They give a reduction in muscle tone and an anticonvulsant effect (reduction in epilepsy)
Why are short acting BZDs better for use as hypnotics?
- They are preferred because their sedative effects will have worn off by the day time
Give 3 examples of BZDs
Midazolam (short) - premedication/induction
Temazepam (medium) - hypnotic
Diazepam (long) - anxiolytic and used to treat alcohol withdrawal
What are Z-drugs?
- Act at the BZD site on the GABA receptor - also stabilise the binding site to increase the affinity
- Structurally different to BZDs
- Hypnotics - NO ANXIOLYTIC EFFECTS
Why does going cold turkey from BZDs after tolerance cause seizures?
- When on the drug, GABA receptors will be getting much more stimulation than normal, hyperpolarising the membrane and reducing the amount of firing
- After a while, the synapse will insert more Glutamate receptors to deal with the increased stimulation / lack of firing
- When you come off of the drug, the GABA receptors wont be stimulated much, however, there will still be more Glutamate receptors
- less inhibition for the increased stimulation –> lots of AP firing
- Symptoms get worse than before
Why would you take BZDs for alcohol tolerance?
- A healthy person has a balance of excitation and inhibition
- Alcohol increases inhibition as it increases GABA’s effects
- When you become tolerant to alcohol, the body upregulates the glutamate receptor to cause more excitation
- If you completely remove alcohol, then you get way more stimulation than inhibition –> seizures
- Therefore you can take BZDs to give some GABA stimulation to provide more inhibition
Summary of BZDs
INCREASE INHIBITION TO DECREASE EXCITATION
Where does Serotonin act?
- Acts on 5-HT metabotropic receptors
- there are 7 families of these
- Serotonin is metabolised in synapses by Monoamine oxidase (MAO) and recaptured by selective reuptake transporters (SERT)
What is the mechanism of 5-HT1A agonists?
- 5-HT1A receptors are found presynaptically
- They are auto-inhibitory receptors - once the neuron releases serotonin, it shuts it off so more cannot be released
- they are found in areas that deal with mood, sensation, cognition and memory processing - work to decrease their innervation
Give an example of a 5-HT1A agonist
Buspirone
- used for GAD
- long-term disorder so wouldn’t use BZDs
- Low risk of tolerance and withdrawal symptoms
Summary of 5-HT1A agonists
DECREASE THE SEROTONERGIC DRIVE
Different types of adrenoceptors
a1 = Gq –> PLC
a2 = Gi –> inhibits AC
B1 + 2 –> Gs –> activates AC
How is the NA removed from the synapse?
Metabolised by monoamine oxidase (MAO)
Recaptured by a selective NA active transporter (NERT)
Give an example of a beta adrenoceptor agonist
Propanolol
How do beta blockers help with anxiety?
They combat the peripheral symptoms of anxiety
- reduce blood pressure by reducing renin release by juxtoglomerular cells (b1 and b2)
- reduce HR by reducing contraction and conduction (b1)
B-blocker summary
DECREASE PERIPHERAL MANIFESTATIONS OF ANXIETY
How are anti-histamines hypnotics?
- histamine causes arousal in the brain
- drowsy AHs are lipophilic so can cross the BBB and reduce the arousal
- ANTIHISTAMINES ANTAGONISE CNS H-RECEPTORS RESPONSIBLE FOR WAKEFULNESS
