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
Lemon balm herbal
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
Kava Kava
Herb
Insomnia
Possibly hepatotoxic
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
What are anxiolytic agents used for?
Anxiety
What is anxiety?
Fear or apprehension of something dreadful
When does anxiety need to be treated?
When it interferes with normal life
When it interferes with part of another disease
Feelings of anxiety
-Uncomfortable feeling of vague fear or apprehension, accompanied by characteristic physical sensations:
-Mental features: worry, fear, impaired concentration
-Physical features: racing heart, shortness of breath, pacing
We need anxiety to do some things, but if it is too strong then we have a problem. To perform your best/stay alert, it is best to have ___% of anxiety.
20-30
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? (intentionally put these away so it is easier to focus)
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)–if no fear ever, the brain amygdala region does not light up–NO anxiety/fear
GABAergic system in 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 for 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
Hyperregulation
Suppression after treatment in PTSD
Drug tx for anxiety
Benzodiazepines (quick acting, effective)-target GABA-A
Antidepressants (SSRIs, SNRIs, TCAs, take weeks–very slow acting which is bad because it does not help depressed pts quickly); new breakthrough: ketamine (nasal spray esketamine, very quick acting, game changer)
Buspirone (BuSpar®)
Beta Blockers
Buspirone
-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)
Partial agonists only give ___ effect
Partial; this is good because pts normally don’t need 100% effect and 100% effect can sometimes be bad.
Beta blocker: propranolol
Uses (may need test dose initially)–if dose too high, you go to sleep
Social Anxiety
-PTSD — Nightmares
-CNS Penetration — Lipophilic
-Decreased Peripheral Symptoms of Anxiety (ex: sweating)
Monitor Cardiovascular Effects
-Heart Rate
-Blood Pressure
Side Effects
-Hallucinations
-Vivid Dreams
-Lethargy
-Impotence
**MUST titrate
Miscellaneous anxiolytic: Hydroxyzine (Vistaril)
Histamine H1 antagonist
Miscellaneous anxiolytic: Clonidine (Catapres)
-Alpha2 Agonist
-Uses: Panic attacks, anxiety associated with withdrawal
Investigational anxiolytic: Serotonin Receptor Antagonist
5HT3 — Ondansetron (Zofran®)
5HT2 — Ketanserin (Unavailable in the US)
Investigational anxiolytic: GABA uptake blocker
Tiagabine (Gabitril®)
Investigational anxiolytic: Partial Benzodiazepine Receptor Agonists
No drugs yet :)
Investigational anxiolytic: Glutamatergic agents
-NDMA receptor modulators: d-cycloserine, memantine
-mGluR5 antagonist: fenobam
-mGluR2/3 agonist: LY354740
