Anxiolytics and Hypnotics

Prof. Trevor G Smart

The Scream by Edvard Munch 1893 Insomnia by Steve Crisp

 PLAN

Classifying Anxiety and

Sleep Disorders
Neurotransmitter receptors:
Neural circuits involved
drug targets for
Anxiety and Sleep
The key neurotransmitters
Disorders
G-protein coupled
GABA inhibition
receptors and Anxiety
Endogenous anxiolytic
Serotonergic & Adrenergic
molecules
systems

‘Other’ & ‘Historic’ Drugs

What are Anxiolytics and Hypnotics:
• Drug treatment of anxiety, stress and sleep disorders

• Act mostly in the central nervous system

• Excessive fear response and worry that disrupts everyday function and causes distress

Numbers:
• Approx 3-4 Million cases of anxiety diagnosed in the UK each year.

• Up to 30% will experience anxiety during their lifetime

• Anxiety is the most common of all mental health disorders

• 16 Million adults suffer from sleep disorders

 What are Anxiety and Stress disorders?
Diagnostic and Statistical manual of Mental disorders 5th Ed (DSM - 5)

Panic disorders (PD) - unexpected panic attack, worry over future attack, symptoms
of racing heart rate, short breath, paraesthesia, 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 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

Brain wiring involved in Anxiety and Stress disorders

Cortex
Sensory
system
(Arousal)

medial prefrontal Thalamus

cortex (mPFC)
hypothalamus

Amygdala
Limbic
system
(Emotion) Hippocampus

Brainstem

Increased glutamatergic activity – Physiology: Heart, Respiration rate, Behaviour

Treatment - Increase inhibition
 Anxiety involves several neurotransmitters

Ionotropic receptors:

GABA – Major inhibitory transmitter via GABAA and GABAB receptors

Site of action for barbiturates and benzodiazepines

Increasing GABAergic activity reduces anxiety
Ubiquitous distribution throughout brain
Drug target

Glutamate – Major excitatory transmitter via AMPA(R), NMDA(R) and metabotropic

receptors (mGluRs)

Complex, both potentiation/inhibition of NMDARs confers anxiolysis

No approved drugs
G-protein coupled receptors:

Serotonin (5-HT) – Projections from the Raphe Nucleus to forebrain

Increased serotonergic drive reduces anxiety
Large receptor family (14 subtypes)
Agonists at 5-HT1A receptors are anxiolytic

Noradrenaline (norepinephrine) – Projections from Locus Coeruleus (pons) to forebrain

Upregulated in anxiety – mediates ‘physiology of anxiety’
Antagonists of β-adrenoceptors are anxiolytic
Receptors as therapeutic targets:

GABAARs > 5-HTRs > Adrenoceptors

 GABA Pharmacology – Anxiety and Insomnia
Benzodiazepines – bind to GABAA receptors (GABARs)
- increase inhibition at synapses

Inhibitory Synapse +Benzodiazepine ( )

Inhibitory neuron
Benzodiazepine
GABA GABA
binding site

Cl- abg Cl- abg

b b
Cell membrane ag ag
Hyperpolarisation Frequency
Cl-
& Excitation Cl- channel
opening
Benzodiazepines: Positive allosteric modulators at GABA ARs

Cl- Cl-
GABAA + GABA + BDZ
receptor

+ BDZ
Benzodiazepines: Inverse agonists
Negative allosteric modulators at GABAARs

+ b-carboline + GABA

Cl-

+ GABA + b-carboline
Benzodiazepine antagonist: Flumazenil

Cl-
+ BDZ
+ GABA

+ b-carboline
 Benzodiazepines: structure and effects
CH3
2
3 H
Sedation (anxiolytic)
Hypnosis
dia
Benzo epine
Muscle relaxation
1 z
Cl - Anti-convulsant
Amnesia
4 H

Diazepam
 Uses of Benzodiazepines
BDZ ~Duration (hrs) Active metabolite Uses
Amnesic, pre-Med
Midazolam (t1/2 ~3hrs) 4 -OH
Surgery (endoscopy)
Lorazepam
Oxazepam Anxiolytic
15
Temazepam Hypnotic

Alprazolam (t1/2 ~12hrs) -OH Anxiolytic, panic attks.

24 Hypnotic
Nitrazepam

Chlordiazepoxide (Librium) Anxiolytic, Muscle relax.

~48
Diazepam (Valium) (t1/2 ~20hrs) Nordiazepam Anticonvulsant (diazepam)
(- Me; + =O)
Clonazepam Anticonvulsant, anxiolytic
~60
Flurazepam (t1/2 ~1hr) Desmethyl Anxiolytic
(- Me)
 Anxiolytic / Sedative / Hypnotics – Z drugs
Non-benzodiazepines – act at BDZ binding site on GABAA receptors

1. Zolpidem – Hypnotic Pyridine

Imidazo
Imidazopyridines
2. Zopiclone – Hypnotic

Eszopiclone - Hypnotic Cyclopyrrolones

Pagoclone - Anxiolytic
Suproclone - Anxiolytic
pyrimidine pyrazolo
3. Zaleplon - Hypnotic
(All short t1/2 2 – 7 hrs; reversed by flumazenil) Pyrazolopyrimidines
 BDZ adverse-/side-effects
Unwanted side-effects:
• Confusion
• Drowsiness
• Forgetful
• Muscle incoordination
• Day after impairment
• Driving, manual skills
Tolerance:
• Factor of receptor occupancy
• Factor of dose duration
• Surface receptor numbers?
Toxic adverse effects:
• Overdose
• Prolonged sleep
• Less dangerous cf. barbiturates
• Respiratory depression with EtOH
• Safeguard of flumazenil
Dependence:
• Major problem in clinical use
• Rebound anxiety
• Tremor
• Loss of appetite
• Disrupted sleep
• Slow onset cf. opioids
• Limited craving
• Gradual withdrawal
 Tetrahydro-deoxycorticosterone
Natural anxiolytics in the brain?
OH

1. Neurosteroids
O
(allosteric modulator)
CC DD
Anxiolytic AA BB
Sedative/hypnotic
Anticonvulsant OH
Motor incoordination Allopregnanolone

Glia
Stress responses
Premenstr. stress disorder Neurosteroids
Sleep regulation
GABA
Neuronal development
Ethanol/Drug intoxication Cl- Cl- Cl-
Catamenial epilepsy
Depression, Pain b
ag
2. Diazepam binding inhibitor protein (DBI, 10 kDa)

Endozepines (peptide, 4-6 kDa)

a
Structures? b b
a g
Thalamic reticular nucleus

Endozepine BDZ
Other anxiolytics – the Serotonergic System

Basal
ganglia
5-HT1ARs
(inhibitory Thalamus
autoreceptors)
Hypothalamus
Hippocampus
Amygdala Raphe
nuclei

5-HT1AR – Postsynaptic inhibition (Gi/Go, inhibits adenylate cyclase)

Buspirone – 5-HT1AR partial agonist

• Desensitises presynaptic 5-HT1ARs?

• Very slow onset (weeks)
• Effective for generalised anxiety disorder
• Not for phobias

• Less problematic side effects cf. to BDZs –

• Dizziness
• Headache
• Nausea
 Serotonin and anxiety
Normal

5HT inhibition
5HT1A Rs 5HT
Postsynaptic
5HT Rs

Acute
5HT / inhibition
Buspirone
5HT
5HT Rs

Chronic

5HT /
Buspirone
inhibition
Desensitised 5HT 5HT Rs
5HT1A Rs
 Other anxiolytics – the Adrenergic System

b adrenoceptor antagonists Cingulate gyrus

Propranolol – Thalamus

Anxiety with clear physical signs

• Sweating
• Tremor
• Tachycardia
Amygdala
• Peripheral autonomic effects
Locus To
coeruleus hippocampus
 Other hypnotics

• Chlormethiazole (acts via GABA receptors)

• Used as hypnotic only for elderly – no hangover effect

General advice on use of hypnotics –

• Short term treatment with hypnotics preferred

• Tolerance develops over 2 weeks
• Withdrawal – rebound insomnia, vivid dreams - over weeks
 Historical Drugs
1. Barbiturates – Act via GABAA receptors (can directly activate receptor)

• Anaesthesia (thiopental)
• Severe intractable insomnia (amylobarbitone, secobarbital, butobarbital)
• Epilepsy (phenobarbitone)

Respiratory depression
Not for elderly
Not for sedation

2. Meprobamate – Acts via GABAA receptors

Not recommended, similar to barbiturates, less potent than BDZs, more toxic
(respiratory depression, coma) – MHRA recommendation to avoid use.
Barbiturates: Positive allosteric modulators
& Direct activators of GABAARs

Cl- Cl-
GABAA + GABA + Barbiturate
receptor

Modulation
Cl-
+ Barbiturate

Activation
Non-prescription Anxiolytics / Sedatives:

Antihistamines – H1 receptor antagonists – Sedation, Hypnotic

• Diphenhydramine
• Promethazine

Rapid tolerance

Valerian extract (Valeriana officinalis)

– Valerenic acid

– Potentiates GABAAR function

GABAA receptor viewed from above
GABAA receptor viewed from the side

ALP = Alprazolam