Anxiolytics, Sedatives and Hypnotics Flashcards
Anxiolytics
drugs used to therapeutically treat (inhibit) anxiety disorders and agitation (“motorische Unrhuhe”)
Sedatives
a drug that decreases activity, moderates excitement and calms
Hypnotics
main purpose is to initiate, sustain, or increase time spent in the state of sleep, that resembles natural sleep as defined by EEG, and from which the recipient can be aroused easily
Effect of the optimal drug
Anxiolytics/ sedatives
– The degree of central nervous system (CNS) depression should be the minimum consistent with therapeutic efficacy.
Hypnotics
– Hypnotic effects involve more pronounced depression of the CNS than sedation, and this can be achieved with many drugs in this class simply by increasing the dose.
Nature and biological bases of anxiety and anxiety disorders
-> Abnormal brain physiology involving in particular the amygdala and hypothalamus
- Classes of anxiety disorder (DSM-IV-TR)
– Generalized anxiety (GAD)
– Social phobia
– Specific phobia
– Panic disorder
– Obsessive compulsive disorder (OCD) - Classes of anxiety disorder (DSM-V)
– separation anxiety disorder (in childhood)
– selective mutism (in childhood)
– social anxiety disorder (SAD)
– specific phobia
– panic disorder
– agoraphobia („Platzangst“)
– generalized anxiety disorder (GAD)
– substance/medication-induced anxiety disorder and anxiety disorder due to another medication condition
Nature and biological bases of anxiety
-> SAD, Specific phobia, panic disorder, GAD
SAD: fear of embarssement, rejection, scrutinization
Specific phobia (e.g., for spiders or heights); sensitization enhanced and/or habituation decreased.
Panic disorder: seemigly unproked, full-blown alarm reactions (recurrent panic attacks)
GAD: excessive & relentless („unaufhörlich“) worry; irritable, keyed up („gespannt“), on edge („nervös“), fatigued („erschöpt“), trouble concentrating, maintaing attention; interferes with day-to- day activities
Different kinds of anxiety disorders
- major depressive episode -> 14 years
- generalized anxiety disorder -> 14 years
- panic disorder -> 14 years
- broad mania -> 15 years
- alcohol use disorder -> 15 years
- substance use disorder -> 16 years
- any mental disorder -> 14 years
Dependent upon time frame
Dependance on other factors, e.g., sex
Anxiety disorder -> finding the biological bases
“Basic research has provided critical insights into the mechanism regulating fear behavior in animals and a host of animal models have been developed in order to screen compounds for anxiolytic properties. Despite this progress, no mechanistically novel agents for the treatment of anxiety have come to market in more than two decades.”
Anxiety disorders -> conditioned fear responses
- Pavlovian fear conditioning, classical conditioning
*Two separate and simultaneous pathways: Quick „low road“ & slower „high road“
*Brain circuits in the amygdala: comprise inhibitory networks of γ-aminobutyric acid-ergic (GABAergic) interneurons; GABA plays a key role in the modulation of anxiety responses both in the normal and pathological state. - GABAergic network
- Subtypes of inhibitory interneurons
- Corticotropin releasing factor neurons interact with the hypothalmus and Locus coeruleus
Inhibitory synapse organizers
- postsynaptic and transsynaptic scaffolding proteins
- Gephyrin & anxiety (?):clustering of GABAARs, binds to GABARs (with α2 & γ2 subunits)
- intracellular signaling pathways
Major brain circuits involved in fear and anxiety
- Amygdala fear circuitry
- Fear learning: amygdala – hippocampus – prefrontal circuitry
Major brain circuits involved in fear and anxiety: role of locus coeruleus prefrontal cortex circuit
- both NE and PFC are extensively involved in anxiety etiology
The locus coeruleus (LC) is in a key position to integrate both external sensory and internal visceral stimuli and influence stress- and fear- related neuroanatomical structures.
A concept for the specific involvement of locus coeruleus - pre frontal cortex (PFC) projection
-> various adrenergic receptors (ARs) in both excitatory and inhibitory PFC neurons across numerous cortical layers pre- and post-synaptically!
-> 3 adrenergic receptors (ARs) in the brain
- G-protein-coupled receptors (GPCR):
α1 Rs: Gq PCR: PLC-DAG-PKC -> ↑[Ca2+]i [ ↓PFC Function]
α2 Rs (Gi): ↓cAMP- PKC…->
↑ coherent bursts of synaptic activity
[ ↑ PFC Function]
β Rs (Gs): ↑ cAMP- PKC-> ↑[Ca2+]i …-> ↑ NE release
A concept for the specific involvement
DEEP SLEEP -> minimal receptor engagement
- unconsciousness
FATIGUE -> slight alpha2-AR engagement
- drowsiness
- inattention
- weak PFC top-down control
- impaired working memory
ALERT, RELAXED -> substantial alpha-AR engagement
- relaxed environmental interaction
- flexible attention
- casual descision-making
- functional PFC top-down control
ALERT, PRESSURED -> substantial alpha2-AR engagement
- significant environmental interaction
- focused attention
- critical decision-making
- functional PFC top-down control
STRESS -> alpha1-AR, beta-AR Engagement
- anxiety, fight/flight
- heightened attention
- deficits in PFC top-down control
- impaired working memory
UNCONTROLLABLE STRESS -> alpha1-AR, beta-AR engagement
- search for escape strategies
- extreme anxiety/psychosis
- loss of PFC top-down control
Major brain circuits involved in fear and anxiety: The role of serotonin
- Impulsivity and behavioral adaption
- social behaviors
- avoidance behavior
- anxiety related behaviors
- reward
- inhibition of panic-like behaviors
- learning and memory
- aversive memory acquisition
polymorphisms in the SERT gene are related to anxiety disorders
(low 5-HT levels)
-> Block SERT
-> Desensitize 5-HT autoreceptors
The role of serotonin
-> Raphe nuclei
- 5HT1AR
RAPHE NUCLEI
- dorsal raphe nucleus (DRN) -> amygdala, frontal cortex (facilitate conditioned fear) -> PAG (inhibit fight/flight reactions)
- median RN -> hippocampus (role in stress responses)
- anxiolytic effect of 5HT1AR (“anxious” phenotypes of 5HT1AR-KO mice and patients with panic disorder and social anxiety disorder
5HT1AR
- presynaptic and postsynaptic
- differential roles (5HT1AR-AR -> anxiety-like behavior vs 5HT1aR agonist buspirone)
-> SERT increased in patients
-> blocking SERT - treatment for GAD, PD, SAD, PTSD
-> increase in serotonergic neurotransmission
Primary treatments (high NE, high 5HT)
First line strategies – actions: SSRIs & SNRIS
(= second generation anti-depressants:↓ toxicity, ↑safety)
*SSRIs: inhibit the reuptake of serotonin (by SERT)
-> ↑ synapt. Spalt
*Stimulation of serotonin autoreceptors (wie 5HTR1A )
-> 5-HT synthesis & release
-> ultimately:
* Downregulation and desensitization of the ARs after 2- 6 weeks (future challenge!)
* reduced expression of SERT
*SNRIs: serotonin norepinephrine reuptake inhibitors (venlafaxine)
*Inhibit SERT and NET
*NE -> increased downstream gene expression -> ↑ neurotrophic factors
*SSRIs, SNRIs: Exacerbate anxiety at the start of therapy -> initial low dose
- slow onset of therapeutic action (weeks)
-> often combined initially with benzodiazepines (BZDs)
Other treatments - Buspirone
Actions
*high affinity for 5HT1A receptors - selective partial agonist
*shown in some controlled studies to be effective in the treatment of GAD
*Slow onset of therapeutic action (2-4 weeks; initial inhibition of serotonin release); requires chronic treatment
Partial agonists: Drugs that bind to and activate a given receptor but have only partial efficacy at the receptor relative to a full agonist.
Other treatments - Benzodiazepines
- (site of action: GABAAR; alpha 2 subunit) effective with acute or chronic treatment; but are recommended only for acute treatment
-> Potential for dependence
-> Negative effects on cognition and memory
Other treatments - beta adrenergic antagonists (beta blockers)
e.g. propanolol, nadolol - higher lipophilicity
- peripheral sympathetic effects (as to treat performance anxiety) - effective acutely
- off label use
- side effects, e.g. hypotension
- limited therapeutic indication
Nature and biological bases of anxiety and anxiety disorder
- abnormal brain physiology involving in particular the amygdala and hypothalamus
- anxiety disorder
-> generalized anxiety: Benzodiazepines, SNRIs, SSSRIs, Buspirone
-> social phobia: Benzodiazepines, SNRIs, SSSRIs (performance anxiety)
-> specific phobia
-> panic disorder: Benzodiazepines, SNRIs, SSSRIs, TCA (2nd strategy)
Benzodiazepines
-> sedative, hypnotic/anaesthetic, anticonvulsant, muscle rexant effects
-> impair cognition & memory
-> affect adversely motor control
-> potentiate effects of other sedatives (e.g. alcohol)
Other substances -> Pregabalin
- GABA-analog (Anticonvulsiv)
- Binds to the subunit of a V-dependant calcium channel, α2δ subunit (not to GABA-R!);
presynaptic -> decreases excitatory neurotransmitter release (glutamate, noradrenaline, Substance P) - GAD, SAD (off-label use)
Other substances -> GABAB Rs
- blockade of GABA transminase
- Hydroxyzine (H1-antihistamine, 1st generation; Piperazine derivative)
Other substances -> Phytopharmaca
- LavendelölInteraction with the GABAergic system (≠ BZD binding site)
- Inhibits presynaptic Ca2+channels (NT release)
- Studies available
- Also other potential GABA-modulating phytomedicines
Sleep disturbances
Insomnia - difficulty falling asleep or staying asleep throughout the night
Sleep apnea - abnormal patterns in breathing while asleep
Restless legs syndrome (RLS) - a type of sleep movement disorder
Narcolepsy - characterized by extreme sleepiness during the day and falling asleep suddenly during the day.
- Many drugs can potentially produce sleep disorders
Insomnia
- Problems falling asleep and sleep maintenance
*Early or frequent awakenings
*Unrefreshed feeling after sleep
*Daytime tiredness or sleepiness
*Irritability, depression or anxiety
Insomnia -> Terms
- Sleep onset latency
- NREM sleep - Stages 1, 2, SWS
- REMS
- Sleep cycles
- Total sleep time
- Rebound-Insomnia upon discontinuation
- Evidence is found for a possible causal link between insomnia symptoms and coronary artery disease, depressive symptoms and subjective well-being.
