Lecture 59 - Pharmacology of Anxiolytics and Sedative Hypnotics 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
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
GABAB Receptor Heterodimer
GABAb1 - binding part only
GABAb2 - signal transduction only
Xyrem (sodium oxybate, GHB)
C-I –> Illicit use and C-III –> Medical use (liquid)
Available only to prescribers enrolled in the Xyrem® Patient Success Program®
Actions
– With concomitant stimulant use: Decrease Excessive Daytime Sleepiness; Increase Daytime Wakefulness
– Decrease Cataplexy
Pharmacology
– GABAB, GABAA, and GHB (?) Receptors
Concerns
– Mechanism (?)
– Combined with other agents
– Red Tape
– Abuse and Misuse
Gamma-Hydroxybutyric Acid (GHB)
Street Names
– “Liquid Ecstasy“, “Liquid X”, “Juice”, “Grievous Bodily Harm”, “Scoops”, “Georgia Home Boy”
Background
– 1960’s to Today: Anesthetic, Fat Burner, Growth hormone Promoter, “Raves”, Date Rape, and Bodybuilding
Pharmacology
– CNS Depression –> Dose dependent: Dizziness; Drowsiness; Coma
– Patients often awaken spontaneously
– Prodrugs: Gamma-Butyrolactone (GBL); 1,4-Butanediol
Gamma-Hydroxybutryic Acid Acute effects
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
– Date Rape — Examinations and counseling (liquid, odorless, tasteless, etc)
Ramelteon (rozerem): 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 (Hetlioz): 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
Suvorexant (Belsomra): orexin receptor antagonist
Mechanism of Action
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
FDA Requests Label Change for All Sleep Disorder Drug Products
Including the newer nonbenzodiazepine drugs
– Eszopiclone
– Ramelteon
– Zaleplon
– Zolpidem
FDA required labeling needs to include information about Sleep-Related Behaviors
– Sleep-driving
– Cooking and eating food (while sleeping)
– Making phone calls (while sleeping)
More Sedative Hypnotics
Trazodone
– Antidepressant (lots of targets)
– Hypnotic-Unlabeled/Investigational Use
Antihistamines (OTC Drugs)
– Diphenhydramine
– Doxylamine
– Pyrilamine
Herbal/Natural Sedative Hypnotics
Tryptophan
Melatonin
Lemon Balm
Valerian: hepatotoxicity
Chamomile
Kava Kava
Sedative-Hypnotics Overdose
Incidence and Severity
– Commonly encountered in emergency room
– Benzodiazepines or Z-hypnotics in combination with other agents
Causes
– Suicide and Suicide Gesture
– Drug Abuse
Signs and Symptoms
– Depressed respiration
– Blood Pressure
– Reflexes
– Hypothermia
Treatment
– Supportive Treatment
– Maintain Respiration
– Maintain Cardiovascular Function
– Flumazenil for Benzodiazepines or Z-hypnotics
Introduction and General Considerations for Anxiolytic Agents
Anxiety: Fear or apprehension of something dreadful
Treatment of Anxiety
- When it interferes with normal life
- When it interferes with part of another disease
Types of Anxiety
Generalized 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)
Drug 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?
