Yang Sedatives and Hypnotics Flashcards
Sedative definition
Calms anxiety, decreases excitement and activity, does not produce drowsiness, or impair performance
Anxiolytic definition
Antianxiety, relieves anxiety without sleep or sedation (not all anxiolytics are sedatives)
Hypnotic definition
Induces sleep, implies restful, refreshing sleep, not “hypnotized”, natural sleep (sleep-inducing)
Narcotic definition
Actually means “sleep-producing” now refers to opioids or illegal drugs
Stages of sleep
-Wakefulness
-Non-rapid eye movement (NREM) slow-wave sleep
-Rapid eye movement (REM) sleep
Stages of NREM sleep
-Stage 1: dozing
-Stage 2: unequivocal sleep
-Stage 3: voltage increase, frequency decrease
-Stage 4: delta waves
Factors that regulate sleep
-Age: decreases with age due to changes in activity of reticular formation
-Sleep history: rebound of REM sleep
-Drug ingestion: acute and withdrawal produce rebound effects
-Circadian rhythms: normal sleep cycle
Neurotransmitters that regulate sleep
-Catecholamines
-Serotonin
-Histamine
-Acetylcholine
-Adenosine
-GABA
Neuromodulators that regulate sleep
-Growth hormone
-Prolactin
-Cortisol
-Melatonin
-Endogenous peptides
Targets for sedative-hypnotics on the GABAa receptor/chloride ion channel complex
-Orthosteric site
-Allosteric site
-Channel pore
What binds to the orthosteric site on the GABAa receptor/chloride ion channel complex?
GABA
What binds to the allosteric sites on the GABAa receptor/chloride ion channel complex?
-Benzodiazepines
-Barbituates
-Ethanol
-Gluccocorticoid
What binds to the channel pore on the GABAa receptor/chloride ion channel complex?
Picrotoxin
Benzodiazepine mechanism of action
Facilitate GABA action, increase frequency, require intact GABA system
What do Z-Hypnotics target?
BZ1 receptors of alpha1
Benzodiazepine antagonists for overdose treatment
Flumazenil
Inverse benzodiazepine agonists
B carbolines
Z-hypnotics
-Zolpidem
-Zaleplon
-Eszopliclone
BZDs with slow elimination rates
All have active metabolites
-Chlordiazepoxide
-Diazepam (used for seizures, accumulation of metabolites)
-Flurazepam
-Clorazepate
-Quazepam
-Prazepam
BZDs with intermediate elimination rates
-Alprazolam
-Lorazepam
-Clonazepam (anticonvulsant)
-Oxazepam
-Temazepam
BZDs with rapid elimination rates
-Midazolam
-Triazolam
Characteristics of BZDs with slow elimination
-Active metabolites
-Accumulation
-Drowsiness and sedation
-Useful in patients who “wake up”
Characteristics of BZDs with intermediate to rapid elimination
-Preferable in patients with hepatic problems
-Preferable in elderly patients
-Drugs that alter liver enzymes
-Rapid tolerance
-Rebound insomnia
Benzodiazepine considerations
-Readily absorbed (can be delayed by food)
-Have active metabolites or are converted to active forms
-Increased lipid solubility will increase speed of delivery to brain
-Redistribution to highly perfused tissue may decrease duration of action
-Cross placental barrier and are detected in breast milk
-Extensive protein binding, but not clinically significant
BZD pharmacologic properties
-Anxiolytic
-Decrease in REM
-Decrease stage 3 and 4
-Anticonvulsant activity
-Muscle relaxant
-Cardiovascular and respiratory depression
-Anterograde amnesia
-Unable to recall events that occurred
BZD side effects
-Sedation (confusion, ataxia, daytime sedation)
-Weakness
-Headache
-Vertigo
-Nausea
-Paradoxical effects
BZD precaution and interactions
-Other sedatives
-Alcohol
-Pregnancy/breast-feeding
BZD abuse potential
-Low vs barbiturates
-Small kick
Flumazenil therapeutic use
Treat BZD overdose
Flumazenil dosing
-0.2 mg IV over 30 seconds
-If desired consciousness is not obtained, increase to 0.3 mg IV over 30 seconds
Flumazenil max cumulative dose
3 mg
Flumazenil side effects
-Induce convulsions
-Panic attacks
-Agitation
-Confusion
-Nausea an vomiting
-Headache
Z-hypnotic site of binding
Act at BZD binding site
When to use zolpidem
-Short-term treatment of insomnia
-With difficulty of sleep-onset
-Ambien CR for sleep maintenance
Zaleplon clinical pearls
-Short-term treatment of insomnia (7-10 days)
-Rapid acting, rapidly eliminated
-Little tolerance or dependance
Eszopiclone clinical pearls
-Active enantiomer of zopiclone (50 times greater affinity)
-Treatment of insomnia (approved for long-term use)
How are z-hypnotics metabolized?
CYP3A4 to some extent
Side effects of z-hypnotics
-Daytime drowsiness
-Dizziness
-Ataxia
-Nausea
-Vomiting
Sleep-driving
-Sleep-cooking
-Sleep-eating
-Sleep-sex
-Less negative side effects on sleep-patterns vs BZDs
Illicit sedative/hypnotics that target the benzodiazepine binding site
-Flunitrazepam
-Clonazepam
-Zolpidem
Why is flunitrazepam considered illicit?
-Not available in the US
-Roofies
-DEA recommends changing it to a control schedule 1
-Anterograde amnesia (dangerous aid for sexual assault)
Why is zolpidem considered illicit?
-A-minus and zombie pills
-Dangerous aid for sexual assault
-Teen party drug
Long acting barbiturate use
Anticonvulsant
What are the long-acting barbiturates?
Phenobarbital
Short to intermediate acting barbiturate use
Sedative-hypnotics
What are the short to intermediate acting barbiturates?
Pentobarbital
Ultra short acting barbiturate use
IV anesthetics
Barbiturate sleep physiology
-Comparable to BZD
-Decrease REM
-Slow deep sleep
Barbiturate side effects
-Idiosyncratic excitement and pain
-Cardiovascular depression at high doses
-Respiratory depression leading to death
-Enzyme interactions
-Dependence
-Tolerance
-Abuse
-Withdrawal
-Overdose
-Hangover
-Accumulation
Barbiturate duration of action
Inversely proportional to lipid solubility
Barbiturate mechanism of action
-Bind to all GABAa alpha1-5
-Increase the duration of channel opening
-Direct effects on GABAa channel (high doses)
-Higher risk
Benzodiazepine mechanism of action
-Bind to all GABAa alpha1-5
-Increase frequency of GABAa channel opening
-Medium risk
Z-hypnotic mechanism of action
-Bind to GABAa BZ1 receptors of alpha1
-Increase frequency of GABAa channel opening
-Lower risk
What kind of coupled receptor is GABAb?
Gi/o-coupled receptor
Location of the GABAb receptors?
-Brain
-Limbic system
What does inhibition of GABAb do?
-Presynaptic - decrease Ca2+ conductance
-Postsynaptic - increase K+ conductance
GABAb agonists
-Baclofen
-Gamma-hydroxybutyric acid (GHB)
GABAb antagonists
-Phaclofen
-Saclofen
-2-hydroxysaclofen
Xyrem (sodium oxybate, GHB) clinical pearls
-Liquid form is only used for medical use other forms for illicit use
-Available only to prescribers enrolled in the Xyrem Patient Success Program
Actions of Xyrem
-Decreases excessive daytime sleepiness and increases daytime wakefulness with concomitant stimulant use
-Decrease cataplexy
Xyrem receptor targets
GABAb, GABAa, and GHB rceptors
Concerns regarding Xyrem
-Questionable mechanism of action
-Combined with other agents
-Red tape
-Abuse and misuse
GHB street names
-Liquid ecstasy
-Liquid X
-Juice
-Grievous bodily harm
-Scoops
-Georgia home boy
GHB effects
-Dose-dependent CNS depression
-Patients often awaken spontaneously
Acute effects of GHB
-Loss of consciousness
-Amnesia
-Nausea and vomiting
-Headache
-Seizures
-Death
GHB concerns
-No antagonist
-Use with other sedative-hypnotics - including alcohol
-Amnesia
-Date rape
What are the melatonin agonists?
-Ramelteon
-Tasimelteon
Ramelteon mechanism of action
-High affinity for MT1 and MT2 melatonin receptors
-Receptors located in the suprachiasmatic nucleus (SCN)
Ramelteon metabolism
CYP1A2 substrate
What does ramelteon treat?
Insomnia characterized by difficulty with sleep onset
Ramelteon clinical pearls
-Non-controlled substance sleep aid
-No abuse, withdrawal, or dependency
-Negligible risk for next-day “hangover” effects
Tasimelteon mechanism of action
High affinity for MT1 and MT2 melatonin receptors
What does tasimelteon treat?
Non-24-hour sleep wake disorder in blind individuals
Tasimelteon clinical pearls
Orphan product registration
Orexin receptor antagonists
Suvorexant
Suvorexant mechanism of action
-High affinity antagonist for OX1 and OX2 orexin receptors
-Receptors located in the hypothalamus
-Decrease arousal and attention via receptors in locus coeruleus and the raphe
-Reduce rewarding stimuli (DA release) via receptors that modulate the mesolimbic projections between the VTA and the nucleus accumbens
What does suvorexant treat?
Insomnia
Suvorexant clinical pearls
-Morning impairment likely/possible (use the lowest dose possible)
-Scheduled CIV
What information needs to be included on the labeling of all sleep disorder drug products?
-Sleep-driving
-Cooking and eating food while sleeping
-Making phone calls while sleeping
Miscellaneous sedative drugs
-Trazodone
-Antihistamines
Herbal/natural sedative hypnotics
-Tryptophan
-Melatonin
-Lemon balm
-Valerian
-Chamomile
-Kava kava
Causes of sedative-hypnotic overdose
-Suicide and suicide gesture
-Drug abuse
Signs and symptoms of sedative-hypnotic overdose
-Depressed respiration
-Blood pressure
-Reflexes
-Hypothermia
Treatment of sedative-hypnotic overdose
-Supportive treatment
-Maintain respiration
-Maintain cardiovascular function
-Flumazenil for benzodiazepines or z-hypnotics
What is anxiety?
Fear or apprehension of something dreadful
When to treat anxiety
-When it interferes with normal life
-When it interferes with part of another disease
Types of anxiety
-Generalized anxiety disorder
-Panic disorder
-Social anxiety disorder or social phobia
-Obsessive-compulsive disorder
-Post-traumatic stress disorder
-Anxiety associated with other medical issues (autism, depression, etc.)
Drugs that can induce anxiety
-Cocaine
-Beta agonists
-Psychostimulants
-Corticosteroids
Diseases that can induce anxiety
-CHF
-COPD
-Diagnosis of terminal diseases
What can cause anxiety from withdrawal?
-Antidepressants
-Anxiolytics
-Drugs of abuse
-Cell phone/social media
How does norepinephrine effect anxiety?
-Over-active locus coeruleus-release NE
-Stimulate autonomic nervous system
-Dysregulated in GAD and other types of anxiety
-Projects to the amygdala (fear center)
How does the GABAergic system effect anxiety?
-Normally counteracts/balances stimulatory effects of excess NE
-Hypothesis proposes reduced GABAergic signaling. Agents that increase GABA signaling are anxiolytic
-GABA/glutamate (inhibitory/excitatory) (glutamate is converted to GABA by glutamic acid decarboxylase - GAD in the CNS)
-Involved in GAD and panic disorder
How does serotonin effect anxiety?
-May reflect tone at multiple receptors/SSRIs have efficacy
-Partial agonist of 5HT1A receptors effective
-May involve amygdala and balance with NE
-GAD, panic, OCD, social anxiety
How does corticotropin-releasing factor and the HPA axis effect anxiety?
-Hyperregulation
-Suppression after treatment in PTSD
Drugs used to treat anxiety
-BZDs (quick acting, effective)
-Antidepressants (SSRIs, SNRIs, TCAs, takes weeks)
-New breakthrough: ketamine (nasal spray esketamine, very quick acting, game changer)
-Buspirone (Buspar)
-Beta blockers
Buspirone mechanism of action
-Partial agonist on brain 5HT1A receptors
-Moderate affinity for brain dopamine D2 receptors
Buspirone clinical pearls
-Low abuse potential, no or little withdrawal
-Longer onset of action compared to BZD (adaptive response)
Uses of buspirone
-GAD, social anxiety, comorbid depression
-Adjunct use with OCD, PTSD
-Not good for panic disorders (BZD is much faster)
Which beta blockers are used in anxiety?
Propranolol
Uses of propranolol
-Social anxiety
-Nightmares associated with PTSD
Propranolol clinical pearls
-CNS penetration - lipophilic
-Decreased peripheral symptoms of anxiety
-Monitor cardiovascular effects
Propranolol side effects
-Hallucinations
-Vivid dreams
-Lethargy
-Impotence
Miscellaneous anxiolytics
-Hydroxyzine (H1 antagonist)
-Clonidine (alpha2 agonist)
Investigational anxiolytics
-Ondansetron (5HT3 antagonist)
-Ketanserin (5HT2 antagonist)
-Tiagabine (GABA uptake blocker)
-Partial benzodiazepine receptor agonists
-NDMA receptor modulators: d-cycloserine, memantine (glutamatergic agent)
-mGluR5 antagonist: fenobam (glutamatergic agent)
-mGluR2/3 agonist: LY354740 (glutamatergic agent)
