Anxiolytics Flashcards
What are anxiolytics and hypnotics used for ?
What is their main site of action ?
- Drug treatment of anxiety, stress and sleep disorders
* Act mostly in the central nervous system
What is anxiety ?
Excessive fear response and worry that disrupts everyday function and causes distress.
Name 6 anxiety and stress disorders you know.
Panic disorders (PD) = unexpected panic attack, worry over future attack, symptoms of racing heart rate, short breath, paresthesia, irrational fear. Agoraphobia.
Phobias = Excessive fear triggered by an object (food) or environment (tall buildings, cliffs)
Social anxiety disorder (SAD) = Fear of social gatherings, judgement by others, embarrassment
Generalised anxiety disorder (GAD) = Persistent worry and apprehension from diverse sources, cognitive dysfunction.
Post-traumatic stress disorder (PTSD) = Follows significant trauma, injury, threat to personal well-being typified by re-living trauma, flashbacks, negative mood, disrupted cognition
Obsessive-Compulsive disorder (OCD) = Disturbing worrying thoughts (terrible event will occur) and need for perfection that are offset by engaging in repetitive,
ritualistic behaviour
What are the 3 main types of sleep disorders (insomnia) ?
Transient = noise related factors / shift work patterns / jet lag Intermediate = Emotional or illness related episode Chronic = Psychiatric disorders – anxiety, depression, drugs, alcohol
What brain structures/circuits are affected in anxiety and stress disorders ?
- mPFC
- cortex (e.g. sensory system (arousal)
- thalamus
- hypothalamus
- limbic system = amygdala + hyppocampus (emotion)
Which NT levels are increased in anxiety and stress disorders ?
Therefore, how are these disorders treated ?
Increased glutamatergic activity –> Physiology: Heart, Respiration rate, Behaviour
Treatment –> Increase inhibition
Which NTs are involved in anxiety ?
GABA :
- Major inhibitory transmitter via GABA-A and GABA-B Rs
- Site of action for barbiturates and BDZs
- Increasing GABAergic activity reduces anxiety
- Ubiquitous distribution throughout brain
- Drug target
Glutamate :
- Major excitatory transmitter via AMPA(R), NMDA(R) and mGluRs
- Complex, both potentiation/inhibition of NMDARs confers anxiolysis
- No approved drugs
- 5-HT :
- Projections from the Raphe Nucleus to forebrain
- Increased serotonergic drive reduces anxiety
- Large receptor family (14 subtypes)
- Agonists at 5-HT-1A Rs are anxiolytic
NA :
- Projections from Locus Coeruleus (pons) to forebrain
- Upregulated in anxiety – mediates ‘physiology of anxiety’
- Antagonists of β-adrenoceptors are anxiolytic
Which receptors are preferentially targeted for the treatment of anxiety ?
GABA-A Rs > 5-HTRs > Adrenoceptors
When are BDZs used ?
How do they work ?
BDZs –> used to treat anxiety and insomnia
BDZs –> bind to GABA-A Rs and increase the frequency of the channel opening –> increase inhibition at synapses
Where do BDZs bind on the GABA-A R ?
Between the alpha and gamma subunits.
What does it mean to say that BDZ are positive allosteric odulators at GABA-A Rs?
This means that BDZs can potantiate the action of GABA when it binds to its receptor, but cannot activate the GABA-AR alone.
What is beta-carboline ?
Beta-carboline is a BDZ inverse agonist :
- it competitively displaces BDZ from its binding site
- it prevents GABA from activating the receptor if it is not already present
- it closes the channel if GABA is already present
What is flumazenil ?
What is the difference between this coumpound and beta-carboline ?
Flumazenil is a BDZ antagonist :
- it competitively displaces BDZ from its binding site, but has no effect on the ability of GABA to activate the receptor (unlike beta-carboline)
What are the effects of BDZs ?
- Sedation (anxiolytic)
- Hypnosis
- Muscle relaxation
- Anti-convulsant
- Amnesia
What are the different uses of BDZs ?
What difference in action do these different uses reflect ?
Amnesic, pre-med, surgery (endoscopy) :
- midazolam (duration ~ 4hrs)
Anxiolytic, hypnotic :
- lorazopam, oxazepam, temazepam (~15hrs)
Axiolytic, panic attacks, hypnotics :
- alprazolam, nitrazepam (~24hrs)
Anxiolytic, muscle relax, anti-convulsant :
- chlordiazepoxide (Librium), diazepam (Valium) (~48hrs)
Anticonvulsant, anxiolytics :
- clonazepam, flurazepam (~60hrs)
What are Z drugs ?
Drugs that act as anxiolytics, sedative or hypnotics, and that bind at the BDZ binding site of the the GABA-AR.
Give examples of Z-drugs.
Imidazopyridines : - zolpidem (hypnotic) Cyclopyrrolones - zopiclone (hypnotic) - eszepiclone (hypnotic) - pagoclone (anxiolytic) - suproclone (anxiolytics) Pyrazolopyrimidines - zaleplon (hypnotic)
What is the half-life of Z drugs ?
How can they be reversed ?
All Z drugs are relatively short acting (half-life ~ 2-7hrs).
All are reversed by flumazenil.
What are the adverse effects of BDZs ?
Unwanted side-effects: • Confusion • Drowsiness • Forgetful • Muscle incoordination • Day after impairment • Driving, manual skills Toxic adverse effects: • Overdose • Prolonged sleep • Less dangerous cf. barbiturates • Respiratory depression with EtOH • Safeguard of flumazenil Tolerance: • Factor of receptor occupancy • Factor of dose duration • Surface receptor numbers? Dependence: • Major problem in clinical use • Rebound anxiety • Tremor • Loss of appetite • Disrupted sleep • Slow onset cf. opioids • Limited craving • Gradual withdrawal
Are there natural anxiolytics in the brain ?
Which cells release these ?
Yes, these are called neurosteroids, such as tetrahydro-deoxycorticosterone and allopregnanolone.
These are released by glial cells.
How do neurosteroids work ?
What effects do they have ?
They are positive allosteric modulators of the GABA-AR. Effects : - Anxiolytic - Sedative/hypnotic - Anticonvulsant - Motor incoordination
When are neurosteroids released ?
- Stress responses
- Premenstr. stress disorder
- Sleep regulation
- Neuronal development
- Ethanol/Drug intoxication
- Catamenial epilepsy
- Depression, pain
What is diazepam binding inhibitor protein (DBI, 10kDa) ?
DBI = a protein that is regulated by hormones and is involved in lipid metabolism and the displacement of beta-carbolines and BDZs
What are endozepines ?
Endozepines are endogenous pepyides (4-6kDa) compounds with BDZ like effects (bind the same site of the GABA-AR.
Their expression is particularly high in the thalamic reticular nucleus (nRT).
What is the main serotonergic nucleus in the brain ?
Where does it projects ?
The raphe nuclei in the brainstem.
It projects to a variety of areas, including cerebral cortex, cerebellum, basal ganglia, thalamus, hypothalamus, hippocampus and amygdala.
Which 5-HT R is targeted in the treatment of anxiety ?
The 5HT-1A R = inhibitory auto-receptor, causes psotsynaptic inhibition (Gi/o, inhibits AC)
What is an example of anxiolytic acting at the 5HT-1A R ?
Buspirone = 5HT-1A R partial agonist • Desensitises presynaptic 5HT-1A Rs? • Very slow onset (weeks) • Effective for generalised anxiety disorder • Not for phobias • Less problematic side effects cf. to BDZs : • Dizziness • Headache • Nausea
What is the main adrenergic nucleus in the brain ?
Where does it project ?
The nucleus coeruleus.
It projects to the cerebellum, hippocampus, amygdala, thalamus and cingulate gyrus.
Which drugs action of the adrenergic system can be used as anxiolytics ?
Is what particular contexts are these drugs used ?
Propranolol = a beta-AR antagonist
Used to treat anxiety with clear physical signs
• Sweating
• Tremor
• Tachycardia
Used to regulated peripheral autonomic effects
What other hypnotic is used only for the elderly ?
Why ?
- Chlormethiazole (acts via GABA receptors)
* Used as hypnotic only for elderly because there is no hangover effect
What general advice is given to patients taking hypnotics ?
- Short term treatment with hypnotics preferred
- Tolerance develops over 2 weeks
- Withdrawal – rebound insomnia, vivid dreams - over weeks
What other historical drugs have been used as anxiolytics/hypnotics and are no longer used as such ?
- Barbiturates – Act via GABA-ARs (can directly activate receptor)
• Anaesthesia (thiopental)
• Severe intractable insomnia (amylobarbitone, secobarbital, butobarbital)
• Epilepsy (phenobarbitone)
Respiratory depression
Not for elderly
Not for sedation - Meprobamate – Acts via GABA-ARs
Not recommended, similar to barbiturates, less potent than BDZs, more toxic (respiratory depression, coma) – MHRA recommendation to avoid use.
How are barbiturates different from BDZ in terms of their actions on the GABA-AR ?
Barbiturates : Positive allosteric modulators & Direct activators of GABA-ARs
Barbiturates –> increase the duration of opening of the channel (and not the frequency c.f. BDZs)
What other non-prescription anxiolytics/sedatives exist ?
Antihistamines – H1 R antagonists – Sedation, Hypnotic • Diphenhydramine • Promethazine Problem = v rapid tolerance (~2 days) Valarian extract (Valerianaofficinalis) – Valerenic acid – potentiates GABAR function
