Lecture 10 - Drug action in the CNS - Anxiolytics Flashcards
What does it mean that they all treat mental disorders?
They all affect the central nervous system (CNS)
What does anxiety lead to?
Anticipatory FEAR response, which is often independent of external system
What constitutes the FEAR response?
- Defensive behaviours
- Autonomic reflexes
- Alertness
- Corticosteroid secretion - important in coordination of responses
- negative emotions
Describe features of anxiety disorders
- panic disorder, overwhelming fear with marked somatic symptoms
- social anxiety disorder - struggle with human interaction
- phobias
- post traumatic stress disorder - reoccurring visions of traumatic events
- obsessive compulsive disorder
- generalised anxiety (no clear reason or focus)
Describe animal models of anxiety
- elevated maze or cross - one side open - mouse placed inside and avoids the open side, as it is more dangerous
- light/dark box - small rodents afraid of light - measure time in dark vs light - normal physiological action is to stay in dark (avoid predation_
These are called conflict tests
Describe the GABAa receptor
- 5 subunits
- multiple binding sites - not just GABA
- GABAa receptors are targets for anxiolytics, hypnotics (& anti-convulsants, neurosteroids, some general anaesthetics)
Describe the breakdown of GABAa receptor subunits
- 2 alpha subunits
- 2 beta subunits
- 1 other subunit (e.g. gamma)
Where does a benzodiazepine bind on GABAa receptors?
Elsewhere
What happen when an agonist binds to orthosteric site?
Activates the receptor
What happens when a molecule binds to an allosteric site?
It modifies response to agonist. Critical distinction - when agonist bound to allosteric site on receptor, on its own, in the absence of of agonist bound at orthosteric site, there is no response.
Describe properties of GABAa receptors
- ionotropic receptors
- made up of 5 subunits - influences pharmacology, location and function
- mediate fast inhibitory transmission
- post synaptic
- chloride selective
- activation leads to hyperpolarization and reduction in excitability
- agonist at orthosteric site is muscimol, antagonist bicuculline, picrotocin
- Agonist at ALLOSTERIC SITE - benzodiazepines such as Diazepam (positive allosteric modulator), antagonist at allosteric site is Flumazentil
What subunits can bind benzodiazepine?
- alpha 1
- alpha 2
- alpha 3
- alpha 5
only bind to neurons that have one of these subunits
Describe how animal models of anxiety has allowed identification of drug targets
In the a2 mutant mice, anxiolytic effects of diazepam are largely reduced, demonstrating the importance of a2 containing GABAa receptors in anxiety.
- A single gene expressed in various parts of the brain, can be in control of a complete process, reducing fear
Explain how the physiological effects of Benzodiazepine agonists changes as concentrations increases
- Sedation/anxiolytic
- hypnosis
- anterograde amnesia (can’t form new memories)
- anti-convulsant
- reduction of muscle tone (useful of surgery)
Describe how different subunit compositions cause different effects
Specific GABAaR subtypes responsible for mediating the diverse spectrum of BDZ pharmacological effects.
- e.g. the SEDATIVE actions are known to be mediated by A1-containing GABAaRs, whereas the ANXIOLYTIC actions are mediated by A2-containing GABAaRs.
What do a1-containing GABAaRs mediate?
Sedative actions
What do a2-containing GABAaRs mediate?
Anxiolytic actions
How are benzodiazepines are positive allosteric regulators of GABAa receptors?
- increase activity of GABAa receptors
- increase Cl- current across the membrane (but only in the presence of GABA)
- Benzodiazepine AGONISTS selectively increase the size of GABAa responses
What occurs when there benzodiazepine without the presence of an agonist at the orthosteric site?
Will not lead to a response
Explain modulation of GABAa receptors by benzodiazepines vs barbiturates
Cells attached electrode, allows recording of single GABAa channel activity. Drugs can be added directly to the inside of the electrode.
- Benzodiazepine agonists increase frequency of openings, whole barbiturates, another allosteric regulator, increases duration of openings
What does Benzodiazepine do?
- increase frequency of openings
What do barbiturates do?
- increase duration of openings
What is phenobarbital used for
It isn’t prescribed as an anxiolytic, however it is used to put pets down by shutting down the CNS (central nervous system)
What occurs to the orthosteric site when bound by drug vs agonist
Orthosteric site - bound by drug = closed
Orthosteric site - bound by agonist = open
What do PAMs (Positive allosteric modulators) d0?
PAM stabilize the receptor in state with INCREASED AFFINITY FOR GABA, effectively causes leftward shift in concentration response curve
What do NAMs (Negative allosteric modulators) do?
NAM stabilize the receptor in such a state that has reduced affinity for GABA and therefore effectively remains closed/harder to open
Explain how drugs can act as negative allosteric regulators
Was seen to increase memory, however was also a pro-convulsant
How does the pharmacokinetics of Benzodiazepines determine their therapeutic uses?
- short acting compounds mainly used as sleeping tablets
- intravenous diazepam used to treat status epilepticus
- some benzodiazepines are metabolised to produce active intermediates with very long half-life (e.g. Diazepam)
- 1 tablet of Diazepam can stay in body for 60 hours
Describe the use of Zolpidem
- Half life of 2 hours (can be used to treat insomnia)
What are the adverse effects of Benzodiazepine agonists?
Tolerance - decreased responsiveness to a drug following continuous exposure
- may be overcome by increasing dose
- changed responsiveness of CNS with benzodiazepines, mechanism unknown
- metabolic tolerance common with barbiturates
Misuse
Physical dependence characterized by withdrawal
- increased anxiety, insomnia, CNS excitability, convulsions
- more problematic with drugs with short half-lives - e.g. triazolam may cause daytime anxiety when used to treat sleep disorders
- withdrawal may be alleviated by using slower acting drug
- sleepiness, impaired psychomotor function, amnesia
- additive effects with other CNS depressants - fatal in overdose (e.g. benzodiazepine + alcohol).
Describe the drugs used to treat anxiety
Benzodiazepines - use is now limited
- acute anxiety
- co-administered with anti-depressants during stabilization period
Propranolol (beta-blocker)
Anti-depressants - SSRIs (selective serotonin reuptake inhibitors e.g. sertraline) useful for generalised anxiety, phobias, PTSD and OCD
Buspirone (5HT1A partial agonist) - generalised anxiety not phobias
Atypical antipsychotics - generalised anxiety & PTSD e.g. olanzapine
Anti-epileptic drugs - generalised anxiety e.g. pregabalin
What are new developments for anxiolytics?
EpiVario - mixing psychotherapy & small molecule drugs
Stop long-term memory consolidation from occurring
What are drugs used to treat insomnia?
- drug choice depends on underlying cause and whether short-term or chronic (short acting benzodiazepines - e.g. lorazepam and Z-drugs e.g. zolpidem)
- melatonin receptor agonists
- orexin receptor antagonists
- over the counter sleep aids - H1 receptor antagonists i.e. Anti-Histamines
