Lecture 59 - Pharmacology of Anxiolytics and Sedative Hypnotics

Question 1

GABAB Receptor: Metabatropic Receptor

Answer 1

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

Question 2

GABAB Receptor Heterodimer

Answer 2

GABAb1 - binding part only
GABAb2 - signal transduction only

Question 3

Xyrem (sodium oxybate, GHB)

Answer 3

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

Question 4

Gamma-Hydroxybutyric Acid (GHB)

Answer 4

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

Question 5

Gamma-Hydroxybutryic Acid Acute effects

Answer 5

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)

Question 6

Ramelteon (rozerem): melatonin agonist

Answer 6

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

Question 7

Tasimelteon (Hetlioz): melatonin agonist

Answer 7

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

Question 8

Suvorexant (Belsomra): orexin receptor antagonist

Answer 8

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

Question 9

FDA Requests Label Change for All Sleep Disorder Drug Products

Answer 9

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)

Question 10

More Sedative Hypnotics

Answer 10

Trazodone
– Antidepressant (lots of targets)
– Hypnotic-Unlabeled/Investigational Use
Antihistamines (OTC Drugs)
– Diphenhydramine
– Doxylamine
– Pyrilamine

Question 11

Herbal/Natural Sedative Hypnotics

Answer 11

Tryptophan
Melatonin
Lemon Balm
Valerian: hepatotoxicity
Chamomile
Kava Kava

Question 12

Sedative-Hypnotics Overdose

Answer 12

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

Question 13

Introduction and General Considerations for Anxiolytic Agents

Answer 13

Anxiety: Fear or apprehension of something dreadful
Treatment of Anxiety
- When it interferes with normal life
- When it interferes with part of another disease

Question 14

Types of Anxiety

Answer 14

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)

Question 15

Drug and Disease-Induced Anxiety

Answer 15

Drugs
– Cocaine
– Beta Agonists
– Psychostimulants (caffeine)
– Corticosteroids
Diseases
– CHF
– COPD
– Diagnosis of Terminal Diseases
Withdrawal
– Antidepressants
– Anxiolytics
– Drugs of Abuse
– Cell phone/social media?

Question 16

Neurotransmitters and Anxiety: Norepinephrine

Answer 16

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)

Question 17

Neurotransmitters and Anxiety: GABAergic System

Answer 17

GABAergic System
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

Question 18

Neurotransmitters and Anxiety: Serotonin

Answer 18

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

Question 19

Neurotransmitters and Anxiety: Corticotropin-Releasing Factor (CRF) and the HPA Axis

Answer 19

– Hyperregulation
– Suppression after treatment in PTSD

Question 20

Drug Treatment

Answer 20

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

Question 21

Buspirone (Buspar)

Answer 21

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)

Question 22

A partial agonist can

Answer 22

antagonize a full agonist

Question 23

Beta Blockers

Answer 23

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

Question 24

Miscellaneous Anxiolytics

Answer 24

Hydroxyzine (Vistaril®)
– Histamine H1 Antagonist
Clonidine (Catapres®)
– Alpha2 Agonist
– Uses: Panic attacks, anxiety associated with withdrawal

Question 25

Investigational Anxiolytics

Answer 25

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