Anxiety & Sleep Flashcards
What are some clinical uses of hypnotics and anxiolytics?
- relief of anxiety states
- induction of sleep and sedation
- control of withdrawal states in addiction
- muscle relaxation
- severe behavioural disturbance
What is the sleep wake cycle mediated by?
Suprachiasmatic nucleus in the hypothalamus to control circadian rhythm
- neurons increase activity during light phase
- increase in melatonin in dark phase
What neural projections control wakefulness?
Cholinergic systems
Monoaminergic Projections
What parts of the cholinergic system control wakefulness?
- pedunculopontine (Ach)
- laterodorsal tegmental nuclei (Ach)
Which parts of the monoaminergic projections control wakefulness?
- locus coeruleus (noradrenaline)
- raphe nuclei (serotonin)
- tuberomammillary nucleus (histamine)
What neural projections affect sleep?
GABA and Galanin neurons
- ventrolateral preoptic nucleus
Which neurotransmitters maintain wakefulness?
Noradrenaline Dopamine Histamine Acetylcholine Orexin
Which neurotransmitters promote sleep?
GABA
Galanin
Melatonin
Adenosine
Why does caffeine keep you awake?
Blocks adenosine which promotes sleep
How long does a sleep cycle last?
- last 90 minutes
What are the phases in a normal sleep cycle?
REM - rapid eye movement phase
NREM - non-rapid eye movement phase
SWS - slow wave sleep (a type of NREM)
What is the relationship between sleep and memories?
Sleep consolidates memories through gene expression changes
What are the 3 types of insomnia? What are some examples?
- transient (jet lag)
- ST (associated with illness/bereavement stress)
- chronic (lasts longer than 3 weeks)
What may sleep be an early sign of?
Neurodegeneration
What are the current treatments for insomnia?
Benzodiazapines (short acting) (end in pam) and Z drugs (longer acting)
Which drugs should be used to treat insomnia in the ST?
Lorazepam
Temazepam
Which drugs should be used to treat insomnia in the LT?
- eszopiclone (Z drug)
- Zolpidem (extended release
(still have short half life)
What do Z drugs target?
Alpha subunits
- alpha 1 (hypnotic role)
- alpha 3 (anxiolytic effects)
Which Z drugs target alpha-1?
Zaleplon/zolpidem
What are some unwanted effects of benzodiazapines when used as hypnotics?
- change in sleep patterns (suppresses deep and REM sleep which is needed for memory tracing)
- daytime sedation (drowsy)
- rebound insomnia
- tolerance
- dependence (withdrawal syndrome)
What are the withdrawal symptoms of benzodiazapines when used as hypnotics?
- anxiety
- nausea
- muscle cramps
- seizures
Why is excessive hypnotic use bad?
Can create a spiral of dependence
- prolonged prescription needs to be avoided
- can switch to non-pharmacological treatment (CBT)
What drug has recently been used for insomnia?
Pregabalin - binds to alpha2delta subunit of voltage gated calcium channels, also used as anxiolytics, no disruption of sleep patterns, no tolerance
What is the orexin system?
- effects mediated by orexin OX1 and OX2 receptors
- wide distribution of projections
- regulates arousal, appeitie and wakefulness
What is orexin?
Hypocretin
Peptide produced in the hypothalamus
2 types - A and B
What does a deficiency of orexin entail?
- narcolepsy (excessive sleepiness)
What are some orexin antagonists?
Suvorexant
decreases wakefulness
What are the effects of suvorexant?
- morning sedation
- sleep paralysis
- decreased amnesia
- decreased confusion
What are some anxiety disorders?
Panic disorder Social phobia Agoraphobia - fear of open spaces OCD Post-traumatic stress disorder Simple phobia - spiders/blood/needles
Which structures are involved in anxiety disorders?
Limbic - amygdala, insula, anterior cingulate, prefrontal cortex, thalamus, HPA axis
What neurotransmitters are involved in anxiety disorders?
Monoaminergic systems
GABAergic systems
How is the amygdala involved with anxiety?
Hyperactivity of amygdala and limbic structures = fear/anxiety
Which genes are associated with panic disorders?
COMT CCK CCKb (CCK receptors) 5-HT2 receptor MOAa Adenosine A2 receptors
What are the classes of anxiolytics?
Benzodiazepines 5-HT1a agonists (partial agonists) SSRIs SNRIs Beta adrenoreceptor antagonists
Which drugs are benzodiazepines?
Clonazepam
Alprazolam
Lorazepam
Diazepam
Which drugs are 5-HT1a partial agonists?
Buspirone
Ipsapirone
Which drugs are SSRIs?
Fluoxetine
Escitalopram
Paroxetine
Which drugs are SNRIs?
Venlafaxine
Duloextine
Which drugs are beta-adrenoreceptor antagonists?
Propanolol
What are the properties of the GABAa receptor?
- post synaptic
- fast inhibitory transmission = hyperpolarisation through Cl- influx which is higher extracellular than IC
- stops propagation of electrical activity in the cerebral cortex
- extreme heterogeneity = multiple subunit combinations
- binding site for benzodiazepine (positive allosteric modulator)
What is the effect of benzodiazapines on GABA receptors?
- positive allosteric modulators
- potentiates hyperpolarisation = open state frequency and duration increases
- barbiturates also do this to GABAa channel
What is flumazenil used for?
Overdose of benzodiazepines
- antagonists of benzodiazepine binding sites
- but has short half life so need to keep injecting until patient is safe
What is the treatment for generalised anxiety disorder?
- buspirone
- SNRI (venlafaxine, duloxetine)
- SSRI (fluoxetine, escitalopram)
- anti-psychotic drugs (risperidone, quetiapine, olanzapine)
Why have barbiturates become obsolete in treating anxiety?
- major risk of drug dependence
- tolerance dev.
- induction of liver microsomal enzymes (drug interaction risk)
- if overdose = fatal toxicity (respiratory depression)
- accumulation = drowsiness, disorientation, ataxia, slurred speech
- withdrawal syndrome = agitation, insomnia, depression, tension, seizures
What are the unmet clinical needs in generalised anxiety disorder?
- drugs with fast mechanism of action/efficacy
- drugs with broad spectrum of benefits
- drugs leading to improved rates of remission
- devoid of withdrawal symptoms
- fewer adverse drug interactions
- safe for elderly
What are some complications of benzodiazepines for the elderly?
- psychomotor impairment
- risk of falls
- daytime drowsiness
- intoxication
- amnesia
- depression
- respiratory problems
- abuse and dependence
How can we make Z drugs more selective in the future?
- those targeting alpha1 subunit have hypnotic role
- targeting alpha3 subunit have more anxiolytic effects
