SEDATIVE, HYPNOTICS, and ANXIOLYTIC Flashcards
GABAB Receptor: Metabatropic Receptor
Gi/o-coupled receptor (inhibitory)
Heterodimers
Two related seven-transmembrane domain receptors subunits: GABAB1, GABAB2
Location: Brain, Limbic System
Inhibitory: Presynaptic Decrease Ca2+ conductance, Postsynaptic Increase K+ conductance
Xyrem® (Sodium Oxybate, GHB)
Actions
– With concomitant stimulant use…
Decrease Excessive Daytime Sleepiness
Increase Daytime Wakefulness
– Decrease Cataplexy
Gamma-Hydroxybutyric Acid (GHB)
CNS Depression Dose dependent: Dizziness, Drowsiness Coma
Patients often awaken spontaneously
Prodrugs Gamma-Butyrolactone (GBL)
1,4-Butanediol
Acute Effects: Loss of Consciousness and Reflexes, Amnesia, Nausea and Vomiting
Headache, Seizures, Death
Concerns Supportive Treatment — No antagonist
Other Sedative-Hypnotics — Including alcohol
Amnesia
Ramelteon (RozeremTM)
Melatonin Agonist
Mechanism of Action: High affinity for MT1 and MT2 melatonin receptors
Receptors located in the suprachiasmatic nucleus (SCN)
Serves as the “master clock” by regulating circadian rhythms — Loss of melatonin in aging and Alzheimer’s
Metabolism: CYP1A2 substrate
Treatment of insomnia characterized by difficulty with sleep
onset
Non-Controlled Substance sleep aid
No abuse, withdrawal, or dependency
Negligible risk for next-day “hangover” effects
Tasimelteon (HetliozTM)
Melatonin Agonist; Mechanism of Action
High affinity for MT1 and MT2 melatonin receptors
Treatment of Non-24-hour sleep wake disorder (non-24) in blind individuals
Orphan product registration
more sedative hypnotics
Trazodone
Antihistamines (OTC Drugs)
– Diphenhydramine
– Doxylamine
– Pyrilamine
Suvorexant (Belsomra)
Orexin Receptor Antagonist
High-affinity antagonist (sub nanomolar) 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.
Treatment of insomnia
Morning impairment likely/possible (use the lowest dose possible)
Scheduled CIV
Tryptophan
Dietary Supplement
– 5HT Precursor
– Withdrawn from market due to contamination
Caused eosinophilia-myalgia
syndrome
Melatonin
– Nutraceutical
– Travelers’ Jet Lag
– Work Shifts — Insomnia
– Sleep Disturbances
– Signs and Symptoms of Overdose
– Ataxia
Drowsiness
Lemon Balm (Melissa officinalis)
Herb
– Use with caution in patients with
thyroid problems
Valerian (Valeriana officinalis)
Herb
Insomnia
Hepatotoxicity has been noted
Chamomile
– Matricaria chamomilla
– Matricaria recutita
– Herb
– Mild Sedative
– Avoid use in patients with a ragweed
allergy
– Use with caution in patients using
cytochrome P450 substrates
Sedative-hypnotic overdose
Signs and Symptoms
– Depressed respiration
– Blood Pressure
– Reflexes
– Hypothermia
Treatment
– Supportive Treatment
– Maintain Respiration
– Maintain Cardiovascular Function
– Flumazenil for Benzodiazepines or Z-hypnotics
Kava Kava (Piper methysticum)
Herb
– Insomnia
– Possibly hepatotoxic
Considerations for anxiolytic agents
tx of anxiety
Types of anxiety
eneralized Anxiety Disorder (GAD)
Panic Disorder
Social Anxiety Disorder or Social Phobia
Obsessive-Compulsive Disorder (OCD)
Post-Traumatic Stress Disorder (PTSD)
*Anxiety Associated with other Medical
Issues (e.g., autism, depression)
Drugs and disease induced anxiety
Drugs
– Cocaine
– Beta Agonists
– Psychostimulants (caffeine)
– Corticosteroids
Diseases
– CHF
– COPD
– Diagnosis of Terminal Diseases
Withdrawal
– Antidepressants
– Anxiolytics
– Drugs of Abuse
– Cell phone/social media?
Neurotransmitters and Anxiety
Norepinephrine (NE) Over-active locus coeruleus-release NE
Stimulate autonomic nervous system
Dysregulated in GAD and other types of anxiety
Projects to the amygdala (fear center)
GABAergic system and anxiety
normally counteracts/balances stimulatory effects of excess NE Hypothesis proposes reduced GABAergic signaling. Agents that increase GABA signaling are anxiolytic
GABA/Glutamate (I/E) balance (Glutamate is converted to GABA by glutamic acid
decarboxylase -> GAD in the CNS)
Involved in GAD and Panic Disorder
Serotonin and 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
Corticotropin-Releasing Factor (CRF) and the HPA Axis and anxiety
Hyperregulation Suppression after treatment in PTSD
Drug treatment of Anxiety
Benzodiazepines (quick acting, effective)
Antidepressants (SSRIs, SNRIs, TCAs, take weeks); new breakthrough: ketamine
(nasal spray esketamine, very quick acting, game changer)
Buspirone (BuSpar®)
Beta Blockers
Buspirone (BuSpar®)
Partial agonist on brain 5HT1A receptors
Moderate affinity for brain dopamine D2 receptors
Longer onset of action than BZD (adaptive response)
Low abuse potential, no or little withdrawal
Uses
GAD, Social Anxiety, or Comorbid Depression
Adjunct use with OCD, PTSD
Not good for panic disorders (BZD is much faster)
Beta Blockers
Propranolol (Inderal®): Uses (may need test dose initially)
Social Anxiety, PTSD — Nightmares, CNS Penetration — Lipophilic
– Decreased Peripheral Symptoms of Anxiety
– Monitor Cardiovascular Effects: Heart Rate Blood Pressure
– Side Effects
Hallucinations
Vivid Dreams
Lethargy
Impotence
miscellaneous Anxiolytics
Hydroxyzine (Vistaril®)
– Histamine H1 Antagonist
Clonidine (Catapres®)
– Alpha2 Agonist
– Uses: Panic attacks, anxiety associated with withdrawal
what are investigational anxiolytics
Serotonin Receptor Antagonist
– 5HT3 — Ondansetron (Zofran®)
– 5HT2 — Ketanserin (Unavailable in the US)
GABA Uptake Blocker
– Tiagabine (Gabitril®)
Partial Benzodiazepine Receptor Agonists
Glutamatergic agents
– NDMA receptor modulators: d-cycloserine, memantine
– mGluR5 antagonist: fenobam
– mGluR2/3 agonist: LY354740
GABA b receptor targeting drugs
Agonists
Baclofen: Skeletal Muscle Relaxant (treatment of alcoholism)
Gamma-Hydroxybutyric Acid (GHB): Central Nervous System Depressant
Antagonist (mainly research use): Phaclofen, Saclofen, and 2-Hydroxysaclofen
