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.
Demands on an “ideal” hypnotic
-> initiate, sustain, and/or increase time spent in sleep!
*Physiological sleep profile
*Enhance subjective elements of sleep
*Fast onset
*Overdose should not impair CNS function or organs
*No adverse pharmacokinetic properties
* No accumulation
* No hangover
* No loss of efficiency with chronic use
* No withdrawal effect
* No interactions
GABA (γ-aminobutyric acid) - synthesis / neurotransmission
- Inhibitory neurotransmitter
- Synthesis in GAD+ neurons:
Glutamate -> GAD (Decarboxylation) -> GABA - GABA reuptake – GABA transporters (GAT)
- Astrocytes/neurons: GABA-T -> metabolism
GABA (γ-aminobutyric acid) receptors
*ionotropic GABA-A Rs (pentamer structure) mediates fast responses -> Chloride conductance (gCl-)
*metabotropic GABA-B-Rs slow responses -> Potassium conductance (gK+)
selective GABAB receptor agonist: baclofen
* GABA receptors are located at pre- and postsynaptic sites
GABAAR: Pentamer, a chloride permeable ion channel
Location:
Synaptic receptors detect GABA-concentrations in
the mmol-range:
→ postsynaptic Cl- conductance
→fast IPSPs
→post-synaptic hyperpolarisation
Extrasynaptic receptors detect GABA-concentrations in
the μmol-range:
→slow IPSPs
→tonic increase in conductivity
GABAA receptor subtypes
GABAA receptors are heteropentamers,
-5 protein subunits (families)
- 19 GABAA-R receptor subunit genes
α1–6 / β1–3 / γ1–3 / δ / ε / θ / π / ρ1–3
- Subunits in the brain: α, β, γ; several isoforms
*Theoretically possible
~ 2000 different GABAA -receptors
*predominant
~ 20 different GABAA-Receptors
* ~60% of pentamers: 2α1, 2β2 und 1γ2
GABAA R-subtypes and their dynamics
60 % of GABA-A R contains alpha 1 !
alpha1: Cerebral cortex, Cerebellum, Thalamus
alpha2: Hippocampus, Amygdala, Striatum, SPinal cord; Motor neurons
alpha3: Monoaminergic nuclei of the brainstem, cholinergic nuclei in the basal forebrain, thalamus
alpha5: Hippocampus
alpha 1 GABAR
- sedative
- antikonvulsive
- addicitve
- anterograde
- amnesia
alpha 2 GABAR
- anxiolytic
- myorelaxant
- antikonvulsive
alpha 3 GABAR
myorelaxant
alpha 5 GABAR
- myorelaxant
- memory loss
- antikonvulsive
BZD sensitivity
*Bind to a cleft between α and ß subunits
*Pharmacological effects depend crucially on the α subunit isoform
*Only α1-, α2-, α3-, α5- containing GABAR are sensitive to BZDs
Effects on GABAA receptors
Positive allosteric modulators, PAMs, (enhance ICl- )
*Negative allosteric modulators (decrease ICl- ; e.g., competitive antagonist Flumazenil - BZD –Bindungsstelle! Antagonists (prevent and reverse the effect of both types of allosteric modulators)
Benzodiazepines (BZD) - Mechansisms of action
-BZD- are positive allosteric modulators
-bindung produces an allosteric activation of the bindung site for GABA
-The conformational change increases affinity of the GABAAR to GABA
-Increased effectiveness of GABA
-Dose-response curve is shifted to the …
Pharmacodynamic tolerance (GABAR down regulation)
Cross tolerance with alcohol (lengthy conumption of alcoholhigher BZD intake)
Basic chemical structure of BZD
A BZD is comprised of
1. a benzene ring (A) fused to
2. a seven member diazepine ring (B)
All important BZDs contain
3. a 5-aryl substituent ring (C)
Thus, 5-aryl 1,4 benzodiazepines are known as BZDs
Position 7 of ring A is substituted with chloride or nitro group.
There are more than 60 benzodiazepine structures differentiated by duration of action and pharmacokinetic profile. Position 7 is important.
BZDs differ mostly in the speed of onset and duration of drug action
Pharmacokinetics: Absorption
- Common structure, similar mechanism of action
- Differences: onset (lipid solubility) and duration of action (Biotransformation, Redistribution to depots, 3-4 categories = f (Elimination t1/2)
Route of application - often peroral also intravenous, intramuscular oder rectal Absorption
- Oral: BZDs are usu. absorbed completely by the GIT (except clorazepate; rapidly decarboxylated in gastric juice)
- After i.v. administration: quickly distribute to the brain and CNS, rapid uptake (lipid solubility)
Pharmacokinetics: Distribution
- Volume of distribution <- Lipid solubility, binding to plasma proteins, molecular size
- Binding ~ oil:water partition coefficient
- binding to plasma proteins- relatively high, but varies (~70 for alprazolam …99% for diazepam)
- free drug in plasma ~ CSF concentration, BZD penetrate well into the CNS
- rapid uptake in the brain (and other highly perfused organs)
- accumulate in the gray matter, subsequently redistribute into muscle and fat tissue (capacious,
but less well perfused tissue) - Restribution kinetics are complicated by the enterohepatic circulation
- BZD activity is terminated by redistribution similar to that of the lipid-soluble barbiturates
- BZD cross the placenta membranecontained in breast milk
Pharmacokinetics: Metabolism and excretion (ADME)
Metabolism
* most BZDs are extensively metabolized by the hepatic enzyme cytochrome P450 (CYP) families 3A4 and 2C19 [inducers, inhibit; polymorphism]
* Active metabolites of phase 1 can be biotransformed more slowly than the parent compounds
* -> duration of BZD action corresponds less to the t1/2 parent drug
– Extreme example: Quazepam metabolism
Decisive for duration of action: Rate of biotransformation of the drug that is inactivated after the
first metabilic reaction (e.g. triazolamm Midazolam)
Elimination
* After conjugation with glucuronide (phase II), BZDs are excreted almost entirely in the urine
* Reabsorption in the intestine (enterohepatic circulation)
* Reabsorption can be influenced by food intake
Benzodiazepines: Therapeutic use, effect on EEG & sleep structure
- Anxiolytic -> long t1/2; despite danger of accumulation
- Anticonvolusants -> long t1/2, rapid brain entry
- Ideal Hypnotic -> rapid onset @night; sustained action during sleep; no residual action- morning/day
BZDs and sleep
* Decrease sleep onset latency and N1
* Fewer awakenings
* Increase arousal threshold
* Increase total sleep time
* Decrease SWS
* Increase N2
* Decrease REM sleep periods, increase the nr. of sleep cycles
* Rebound insomnia when discontinued
Z compunds
-> Novel-benzodiazepine receptor agonists: sedative hypnotics
*Structurally unrelated
* Bind relative selectively at GABAA-R, BZD site, subunits:α1»_space; α2 & γ2 *Sedation, hypnotic effect ( α1 ); largely replaced BZD -> insomnia
* low/absent: anxiolytic effect, muscle relaxant, anticonvulsive
* Antagonist: flumazenil
Zopiclone
*T1/2 ~5h sleep maintenance and sleep latency
- Stereoisomer: Eszoplicone (long term treatment)
Zolpidem
T1/2 ~2h sleep onset & maintenance
- infrequent daytime sleepiness or anterograde amnesia
-> no active metabolites
- increased time in N3 sleep
- time in REM sleep
-> increase in sleep spindle power
-> decrease in NREM theta power
Zaleplon
*T1/2 ~1h sleep onset
- peak plasma concentration in 1 h
-> no morning sedation!
-> increases slow wave sleep
-> reduced sleep onset latency
NOT SOLD IN GERMANY SINCE 2010
Z-compunds (Z-hypnotic) - Comparison with BDZ
*largely displaced BZD for insomnia treatment ( dependance, abuse)
*YET: Tolerance after a few weeks
*Dependence when taken > 4 weeks likely; withdrawal symptoms persist often up to six weeks
*anterograde amnesia
*effects during pregnancy: monotherapy at the lowest effective dosage for the shortest possible duration
Benzodiazepine Antagonist
-> Flumazenil
*competitive antagonist of BZDs and Z-hypnotics
*-> shift to the right of the dose-response curve
*with BZD: F. is fast acting (i.v.) after (30-60sec)
However, BZD effects can slowly occur anew within the next hour(s) depending upon the agonist and antagonist half-lives (cp. metabolism, redistribution of BZD)
Indications:
*BZD overdose
*reversal of sedative effects of BZD
* t1/2 ~ 1h
*high „first pass“ effect
Administration modes and the first-pass effect (Presystemic elimination)
The first pass effect: phenomenon in which a drug gets metabolized at a specific location in the body that results in a reduced concentration of the active drug upon reaching its site of action or the systemic circulation.
Barbiturates
Mechanism of action
* main mechanism (at higher doses) -> act directly agonistic (!) at the GABAAR β-subunit
- Barbiturates can induce currents within the GABAA R channel without the presence of GABA
* Lower doses: allosteric effect -> increase opening time of GABAAR
* Inhibit (at high dosages) AMPA-R and (at even higher dosages) voltage dependent cation-channels)
Barbiturates -> ADME -> Distribution
- Usually oral administration
- Rapid absorbtion (~ as Na+ salts)
- Onset of action 10 -60 min (delayed by presence of food)
- Seldom: Intramuscular; intravous (management of status epilepticus or induction/maintenance of general anaesthesia)
Distribution
* Distribute widely; cross the placenta readily
* Rapid redistribution into muscle and fat (less in plasma and the brain) after i.v. injection; e.g., thiopental, methohexital (highly lipid soluble) -> awakening after 5-15 min
Barbiturates -> ADME -> Redistribution
- The exit from the anesthetic influence of this single dose of thiopental is due to redistribution, not metabolism
- The rate of accumulation in the different compartments depends on regional blood flow
- Extent of accumulation reflects the different capacities of the compartments & the elimination
Barbiturates -> Metabolism and elimination
- Nearly complete metabolism or conjugation in the liver (except less lipid-soluble phenobarbital)
- the oxidation of radicals at C5 is the most important biotransforamtion terminating activity
- ~ 25 % (50%) of phenoparbital (aprobarbital) are excreted unchanged in the urine
- More rapid in young than elderly and infants
- t1/2 are increased in pregnancy ( volume of distribution)
- Repeated administration of phenoparbital -> shorter t1/2 (induction of microsomal enzymes
Thiopental - ultrashort acting
*pre-surgical: short narcosis, or to initiate or maintain general anaesthesa
*Highly lipid-solublepasses readily the BBB
i.v. administrationsleep in 10-20 sec
* effect duration 5–15 min (ultra short acting)rapid redistribution from the CNS into fat & muscle depots *elimination t1/2 5–10 h
*Especially in adipositas there is an overlap with the slow redistribution from the tissue (5… 28 h).
Phenobarbital (phenobarbital sodium) -long- acting drug
*less lipid-soluble
*Onset: ~ 1 h
*Action: 10-12 h
*management of status epilepticus (i.v.)
*addiction develops quickly
*elimination t1/2 (adults) 60 – 150 h (long-acting)
Barbiturates - effects on sleep stages and CNS
- Increased total sleep time (TST)
- Decrease in sleep latency & number of awakenings
- BUT also decreases in the duration of REMS and SWS
- Repetitive nightly administration: some tolerance develops
-> decreased TST
-> Rebound on discontinuation - (!) Tolerance to sedative, hypnotic, euphoric effects occurs more readily than to
anticonvulsant and lethal effects - Not used as hypnotics in Germany anymore
The SCN and sleep/wake regulation
The dorsomedial hypothalamus (DMH) inhibits the „sleep center“ and facilitates the lateral hypothalamic (LH) orexinergic system
Melatonin
- Production and release of melatonin are dependent upon the activity of the suprachiasmatic nucleus (SCN).
- Activity of the SCN is influenced by light
- By light the SCN inhibits melatonin production and secretion by the pineal gland
- Melatonin is released in the dark
- Melatonin is synthetized from serotonin
- in the pineal gland
- SCN possess melatonin receptors (MT1R, MT2R), GPCR
- Other brain regions are involved in melatonin production and secretion
Melatonin as an hypnotic
- MTR localization implicates their physiological relevance for sleep regulation (e.g. SCN, reticular thalmus, hippocampus)
Rodents: - MT1KO -> selective SWS disruption, increased W
- MT2KO -> selective REMS disruption, increased NREMS
- MT2R agonist- -> increased REMS
Melatonin congeners -> Ramelteon
*Highly selective MT agonist (affinity: MT1»MT2) [Melatonin: MT2 > MT1]
*In the SCN, MT1R -> promotes sleep onset; MT2R -> shifts timing of the circadain system
*No affinity to other receptor classes (not to BZD-R site, DA, opiate ion channels)
Pharmacokinetics:
*Is absorbed rapidly from the GIT; rapid first-pass metabolism
*Largely metabolized by CYPs 1A2, 2C, 3A4
*R.s M-II metabolite acts as an agonist at MT1 and MT2
*t1/2 ~ 2h
*taken ~ 30 min before bedtime
*No tolerance in its reduction of sleep onset latency (after 6 months)
*Effects on total sleep time are not consisent across species
*No (next-day) cognitive impairment
*No rebound insomnia or withdrawal effects
*Mostly for delayed sleep onset syndrome
Prolonged release melatonin (PRM)
- 2–10 mg, 1–2 h before bedtime
- treatment of insomnia and circadian sleep disorders
Slow wave sleep (SWS) - neuronal control
- Interaction adenosine, VLPOA, orexinergic neurons, brainstem/hypothalamic neuromodulators
Anti wake promoting
* Anti-histamine
* Orexine antagonists
Tricyclic Antidepressant - low dose Doxepin (<6 mg/d)
- Antihistaminergic effects
- At a low dose: only effects the histamine receptor H1R
- At high doses -> inhibits reuptake of serotonin, noradrenalin, antagonizes other activity
- t1/2~15h
- Improves sleep maintenance
Orexin receptor antagonist drug - Suvorexant
- inhibitor of orexin 1 and 2 receptors (OX1R, OX2R; GPCRs)
- DORA (dual orexin receptor antagonist), ORA
- Approved by the FDA in 2014
- promotes NREM and REM sleep -> sleep maintenance
- Reduces sleep onset latency
- allows somnolence indistinct from normal sleep
- Best taken 30 min before bedtime (7h sleep)
- Most common adverse reaction: daytime somnolence
- possibility of worsening depression, suicidal ideation
- Approved by AASM for treatment of insomnia
Orexin receptor antagonist drug - Lemborexant
- DORA (dual orexin receptor antagonist) or ORA
- approved by the AASM in late December 2019
- promotes NREM sleep maintenance
- No effect on REM sleep
- Reduces sleep onset latency
- t1/2 =17 to 19 h
- Most common adverse reaction: daytime somnolence
- Approved by AASM for treatment of insomnia
Other newly approved orexin inhibitors
*Daridorexant (nemorexant), DORA, t1/2 ~6 h
-> … in clinical trials
* Seltorexant (selective orexin-2 receptor antagonist), t1/2 =2 to 3 h
* Adverse effects: headache, dizziness, and somnolence
ORAs -> GpCRs and non-selective cation channels (NSCC)
NSCCS: Macromolecular pores in the cell membrane that form an aqueous pathway enabling cations such as Na+, K+, or Ca2+ to flow rapidly, as determined by their electrochemical driving force, at roughly equal rates.
Alternative methods
- Cognitive behavior therapy (CBT) for anxiety and insomnia
- Perspective of vestibular stimulation for insomnia
- Perspective of rhythmic exogenous (auditory) stimulation for insomnia
- Caution regarding designer BZDs!
- Lifestyle changes
