PHRM845 Exam 4 (Yang) Flashcards
Sedative, hypnotics, and anxiolytics Part 2
Additional Sedative-Hypnotics. Primarily focusing on which receptor?
GABA-B
GABA-B is (metabotropic/ionotropic)
Metabotropic; it is a GPCR
GABA-B is a ____ receptor. This means it is (excitable/inhibitory).
Gi/o-coupled receptor
Inhibitory (increase Cl- influx)
Heterodimers in GABA-B
Two related seven-transmembrane domain receptors subunits
GABAB1
GABAB2
Location of heterodimers
Brain
Limbic System
How do GABA-B receptors impose their inhibitory effect?
Presynaptic-Decrease Ca2+ conductance
Postsynaptic-Increase K+ conductance
Agonists of GABA-B
Baclofen
-Skeletal Muscle Relaxant (treatment of alcoholism)
Gamma-Hydroxybutyric Acid (GHB)
-Central Nervous System Depressant
**These enhance the inhibitory effect of GABA-B
Antagonist of GABA-B
Phaclofen, Saclofen, and 2-Hydroxysaclofen
**Mainly used for research
What does increasing potassium conductance do to a cell?
Hyperpolarizes it
Cataplexy definition
Sudden and transient episode of muscle weakness accompanied by full conscious awareness, typically triggered by emotions such as laughing, crying, terror, etc
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
Xyrem has (no/strong) color and odor
No
Why must prescribers be enrolled in Xyrem patient success programs?
There is huge abuse potential. Get people high which leads to addiction.
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 (with increasing dose; like barbiturates)
-Patients often awaken spontaneously
-Prodrugs
~Gamma-Butyrolactone (GBL)
~1,4-Butanediol
**Combined use with marijuana and alcohol have an unknown effect (AVOID USE)
Acute effects and concerns of GHB
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 (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 (GOOD!)
-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
1. Small population for clinical trial
2. Patent lasts longer
3. Fast FDA approval
Orexin neurons/hypocretin system
The orexin neurons innervate and excite many brain regions that drive arousal and attention, including the locus coeruleus and the dorsal raphe. Rewarding stimuli trigger release of dopamine from the mesolimbic projections between the ventral tegmental area and the nucleus accumbens, and orexins enhance signaling in this pathway. As Brisbare-Roch et al. have found, an orexin antagonist that blocks these signals can promote sleep (by reducing arousal) and possibly aid in the treatment of drug addiction (by dampening reward signals).
Suvorexant (Belsomra): Orexin Receptor Antagonist
Mechanism of Action
-High-affinity antagonist (sub nanomolar) for OX1 and OX2 orexin receptors–so you are not as wakeful
-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 (in history)
Trazodone
-Antidepressant (lots of targets)
-Hypnotic-Unlabeled/Investigational Use
Antihistamines (OTC Drugs)
-Diphenhydramine
-Doxylamine
-Pyrilamine
Concern with herbal/natural sedative hypnotics
They contain less than 1/2 the ingredients that the labels claim–quality is difficult to control
Tryptophan herbal
Dietary Supplement
5HT Precursor
Withdrawn from market due to contamination
Caused eosinophilia-myalgia syndrome
Melatonin herbal
Nutraceutical
Travelers’ Jet Lag
Work Shifts — Insomnia
Sleep Disturbances
Signs and Symptoms of Overdose
Ataxia
