CNS pharmacology I Flashcards
What drugs treat anxiety?
Anxiolytics
What drugs treat insomnia?
Sedatives/hypnotics
Why are similar interventions needed between anxiety and insomnia?
They are closely linked - tend to cause each other
What is anxiety a human manifestation of?
How?
A FEAR response
- It is a defensive mechanism
- Activation of the sympathetic nervous system (fight or flight)
- May get freezing of behaviour/hiding
How is anxiety classified?
What are the different categories of anxiety?
Into categories related to SYMPTOMS and CAUSES
1) Generalised anxiety
2) Panic disorder
3) Phobias
4) PTSD
5) OCD
What is the most difficult anxiety to model? Why?
Generalised anxiety
There is no clear reason behind it
What marked symptoms does a panic disorder have?
Clear somatic symptoms (eg. sweating, increased heart rate)
What is PTSD associated with?
A memory
What is OCD?
Ritualistic/repetitive behaviour
Can be seen in animal models
What are 4 treatments of anxiety?
1) Benzodiazepines
2) Anti-depressants
3) Buspirone
4) Beta-blockers
What are the advantages of Benzodiazepines?
- Calming effect
- Work quickly
What are the disadvantages of Benzodiazepines?
Long-term use:
- Addiction
- Tolerance
- Drowsiness
What are the most common anti-depressants to be prescribed?
SSRIs
What are the disadvantages of anti-depressants?
Take a long time to work
What is Buspirone?
A 5-HT agonist
What are the advantages of Buspirone?
Anxiolytic effects WITHOUT the unwanted side effects of Benzodiazepines
What are the disadvantages of Buspirone?
Take several weeks to start working
What is propanalol?
What does it block? Why is this advantageous?
A beta-blocker
Blocks the PHYSICAL symptoms of the disease, which is enough to get the individual through tough times
How are drugs tested that treat anxiety?
As anxiety is a fear response in animals, can subject model organisms to fear and then treat them with drugs - observe effects
What is the amino acid neurotransmitters that are affected in anxiety?
What is this similar to?
What does this mean?
GABA neurotransmitter
Similar to epilepsy - same neurotransmitter system
This means that some anti-epileptic drugs can be useful in the treatment of anxiety
What do all the treatments for anxiety do?
Interfere with GABA signalling
How many families of GABA receptors are there?
2
What type of receptors are the GABAa receptors?
Ionotropic receptors (ligand gated)
Where are GABAa receptors found?
On the soma and dendrites of neurons in the CNS (postsynaptic)
Where is GABA released from in the brain?
What does it mediate?
From interneurons
Mediates INHIBITION
What is the normal function of GABA release from the interneurons?
To keep the brain in balance
What ion passes through GABAa receptors?
Cl-
What happens when GABAa neurons are open in the postsynaptic membrane?
They HYPER POLARISE the neuron - stopping it from reaching threshold
What superfamily does the GABAa receptor belong to?
What else is a member of this family?
The NICOTINIC receptor superfamily
Ach nicotinic R is also a member of this family
What is the structure of the GABAa receptor?
5 subunits (2 alpha, 2 beta, 1 other)
More than one ligand binding site
How can GABAa receptors vary?
Vary in pharmacology, location and function
- As there are 5 subunits that make up the GABAa receptor
- But can vary in subunit composition (many different genes that code for the different subunits)
- Depending on what subunits make up the receptor –> function, location, pharmacology
What is the traditional site where GABA agonist binds to the GABAa receptor?
What happens when this site is bound?
The orthosteric site
When bound - the channel opens
What are the other drug binding sites on the GABAa receptor?
What happens when drugs bind here?
Allosteric sites
When drugs bind here:
- MODIFIES the behaviour of the receptor, only when the orthosteric site is bound
What drugs targets the drug binding site on GABAa?
How do they act?
1) Diazepam
- Increases the activity of the receptor, underpinning the sedative effects
2) Flumazenil
- Antagonist
3) Beta-Carboline
- INVERSE agonist
- Decreases the responsiveness to GABA
What happens if block GABAa in the brain?
Why?
Convulsions
Excitatory signals are not balanced
Which GABAa receptors are NOT implicated in the treatment of anxiety?
What type of receptors are these?
GABAb receptors
Metabotropic receptors (GCPR)
What are GABAa receptors targets for?
- Sedatives
- Anxiolytics
- Hypnotics
- Anti-convulsants
- Some general aneasthetics
Where does each drug bind to the GABAa receptor?
At DISTINCT sites
How many orthosteric sites of the GABAa receptor must be bound to make the channel open?
2
Which GABAa receptors do Benzodiazepines interact with?
What does this mean?
Only CERTAIN subunits (only receptors with alpha 1,2,3,4 or 5 can respond)
Means that in some parts of the brain - there are GABAa receptors that are INSENSITIVE to Benzodiazepine
What happens in mice if there is a KO of alpha2?
Why?
Mice no longer respond to Benzodiazepine
Due to:
- ONE amino acid change (histadine –> arginine) which removed the Benzodiazepine binding
What are the 5 physiological effects to benzodiazepine agonists?
1) Sedation/Anxiolytic (less responsive to stressful situations)
2) Hypnosis
3) Anterograde Amnesia (Prevent memory of events whilst under the influence)
4) Anti-convulsant
5) Reduction of muscle tone
Describe the action of Benzodiazepines on current through GABAa receptors
In presence of Benzodiazepine - current is INCREASED dramatically
When remove Benzodiazepine - current back to normal
What is the selectivity of Benzodiazepine?
VERY selective, only for GABA receptors
How can you get a bigger current from a channel?
- Increase FREQUENCY of channel openings
- Increase channel OPEN time
- Decrease channel CLOSE time (different mechanisms to increasing channel open time)
- Increase channel CONDUCTANCE - more ions through per unit of time
How does Benzodiazepine cause a bigger current in the GABA receptor?
Make it easier for the the channels to open - increases the FREQUENCY of channel opening times
How do Barbiturates act on GABAa channels?
Increase the opening TIME
What happens if you increase the concentration of Barbiturates high enough?
Channels can open, even in the ABSENCE of GABA (ligand)
When is the effect of Benzodiazepine only ever seen?
In the presence of GABA agonist
Where does beta-carboline act?
What are the effects of this drug in comparison to Benzodiazepine?
Act at the Benzodiazepine site on the GABAa receptor
Is an INVERSE AGONIST - OPPOSES the effects of Benzodiazepine
How does beta-carboline effect the GABAa receptor?
What does this cause?
- DECREASES the frequency of channel opening in the presence of GABA
Causing:
- A smaller current through the GABAa channel
- LESS neurons are inhibited
- May increase learning and memory
What can decreasing GABA activity cause?
Convulsions
What is Flumazenil?
Where does it work?
A COMPETITIVE antagonist with Benzodiazepine for the Benzodiazepine binding site on the GABAa receptor
What is the action of Flumazenil?
No action - only prevents the binding of the agonist
What is the only clinical use for Flumazenil?
To treat the overdose of Benzodiazepine
What are the similarities/differences between some of the Benzodiazepines on the market?
Similarities:
- All work in the SAME way
Differences:
- Slightly altered chemically –> have different pharmacokinetics (how quickly distributed/metabolised)
What are the 2 most widely used Benzodiazepines?
1) Zolpidem
2) Diazepam (Valium)
What is Zolpidem useful to treat/not useful to treat and why?
Useful to treat INSOMNIA:
- Rapidly acting sedative
- Lipophilic - can easily cross the BBB
NOT useful for ANXIETY:
- Short half-life so short duration of action, due to it being rapidly metabolised
What are the advantages of using Diazepam (Valium) to treat anxiety?
Longer half-life
Why does Diazepam have a long half-life?
- When the drug undergoes FIRST PASS metabolism, creates an ACTIVE drug
- This active drug is another Benzodiazepine agonist –> prolonging the activity
What are the disadvantages of using Benzodiazepines?
Long duration of action due to the long half-life
Causing many unwanted side effects:
- Impair motor ability
- Drowsiness
What are 5 the adverse effects of Benzodiazepine agonists?
1) Sleepiness, impaired psychomotor function, amnesia
- -> not good for long term use
2) ADDITIVE effects with other CNS depressants (eg. alcohol) –> fatal in overdose
3) TOLERANCE
4) MISUSE
5) PHYSCIAL DEPENDANCE
What does the dose-response curve for Benzodiazepines show?
- Sedation at low levels
- As dose increase –> go into hypnosis (where plateau on the graph)
Why is there a ‘plateau’ on the dose-response curve of Benzodiazepines?
The drug ONLY modifies and increases the action of GABA in parts of the brain where GABA is active
What happens in a dose-response curve of Barbiturates?
Why?
Anaesthesia, coma, death
In addition to working as ALLOSTEIC agonists, when concentration increases, Barbiturates can have an agonist action against the GABAa receptor
What is ‘tolerance’ to a drug?
Decreased responsiveness to a drug following continuous exposure
What are the 2 difference types of tolerance to a drug?
1) At the level of the RECEPTOR
- Receptor CHANGES so they can no longer bind to the drug
2) METABOLIC tolerance
- Body INCREASES the enzyme that breaks down the drug
What type of tolerance is common with Barbiturates?
Metabolic tolerance
Hoe can tolerance be overcome?
By increasing dose
What is the physical dependance of a drug characterised by?
What is this?
Withdrawal syndrome
An exaggerated response of the problem have in the first place
What are the symptoms of withdrawal syndrome?
- Increased anxiety
- Insomnia
- CNA excitability –> convulsions
With what drugs is the withdrawal syndrome more problematic?
Drugs with short half-lives
What are other anxiolytics and hypnotics that can be used instead of Benzodiazepines?
1) Benzodiazepine PARTIAL AGONISTS
2) RECEPTOR SELECTIVE Benzodiazepine agonists
3) NON-BENZODIAZEPINES
4) Beta-adrenoR antagonists (eg. propanolol)
5) Over the counter sleep aids: anti-histamines
What are the disadvantages of non-benzodiazepines?
- Doesn’t treat depression
- Takes a while to be affective
What are Beta-adrenoR antagonist used for?
To block the PHYSICAL SYMPTOMS associated with the activation of the sympathetic nervous system
Why are benzodiazepine PARTIAL AGONISTS advantageous?
Reduces efficacy –> leads to less tolerance and physical dependance
Why are RECEPTOR SELECTIVE Benzodiazepine agonists advantageous?
Selective to the parts of the brain involved in anxiety
Why are NON-BENZODIAZEPINES advantageous?
- Non-sedative
- Doesn’t have the problems of Benzodiazepines
