Lecture 58 - Sedative, Hypnotics, and Anxiolytics Flashcards
HISTORY AND BACKGROUND
Ancient: Alcohol, opioids, cannabis
1853: Bromides (K+ bromide, Bromo-Seltzer) 1903: Barbiturates widely used, abused, safety 1930s to 1960s: “Non-barbiturates”
1961: 1st benzodiazepine (BZD)
– Chlordiazepoxide –> Safer
Present Day: Large number of benzodiazepines, sedative-hypnotics, anxiolytics, anticonvulsants, muscle relaxants
Sedative
Calms anxiety, decreases excitement and activity, does not produce drowsiness, or impair performance
Anxiolytic
Antianxiety, relieves anxiety without sleep or sedation (not all anxiolytics are sedatives)
Hypnotic
Induces sleep, implies restful, refreshing sleep, not “hypnotized!”, natural sleep (medial use term: sleeping-inducing)
Narcotic
Actually means “sleep producing”, now refers to opioids or illegal drugs
Reticular formation
The reticular formation extends through the central core of the medulla oblongata, pons, midbrain
It is an intricate system composed of loosely clustered neurons in what is otherwise white matter
very complex, contains dopamine, adrenergic, serotonergic, and cholinergic neurons
regulates sleep-wake transitions and synchronization of EEG
SLEEP PHYSIOLOGY
Stages of Sleep:
– Wakefulness
– Non-rapid eye movement (NREM) slow-wave sleep
– Rapid eye movement (REM) sleep
NREM sleep
– Stage 1 (dozing)
– Stage 2 (unequivocal sleep)
– Stage 3 (voltage increase, frequency decrease)
– Stage 4 (delta waves)
REM sleep (similar to awake in EEG)
Sleep Deprivation
– Total Sleep
– Delta Sleep
– REM
Factors that Regulate Sleep
Age: Decreases with age due to changes in activity of reticular formation
Sleep History: Rebound of REM sleep
Drug Ingestion: Acute and withdrawal produce rebound effects
Circadian Rhythms: “Normal sleep cycle”
Biological regulators of sleep
Neurotransmitters (almost all):
– Catecholamines (e.g., epinephrine, norepinephrine, and dopamine)
– Serotonin (5HT)
– Histamine
– Acetylcholine (ACh)
– Adenosine
– GABA (main target for current medications)
Neuromodulators:
– Growth Hormone (GH)
– Prolactin
– Cortisol
– Melatonin — “hormone of darkness”
– Endogenous Peptides
GABAergic Neurotransmission
GABAA receptors
GABAB receptors
GABA transporters (GAT-1)
GABA-T (transaminase)
GABAA receptor/chloride ion channel complex
targets for sedative-hypnotics
Orthosteric site: GABA (alpha1 and beta2)
Allosteric Sites
- benzodiazepine (BZD) site (alpha1 and gamma2)
-Barbiturate
-Ethanol
-Glucocorticoid
Channel pore (picrotoxin)
Ligands Acting at the BZD Receptor
Benzodiazepines: Facilitate GABA action (e.g., alpha1-5), increase frequency, require intact GABA system (internal safety system)
Non-Benzodiazepines (Z-Hypnotics): zolpidem (Ambien®), zaleplon (Sonata®), eszopiclone (LunestaTM) – BZ1 receptors of alpha1
BZD Antagonists: flumazenil (Romazicon®), overdose treatment
Inverse BZD Agonists: B carbolines
Allosteric modulators: MOA
allosteric inhibitor binds to the allosteric site, preventing substrate from binding to active site because it changes the shape of the binding pocket –> little or no products made
Modulation of the GABAA receptor
Ligands acting at “other” non-orthosteric sites
A. BZDs: Increase frequency of channel opening,
B. Barbiturtates (Bbt): Increase duration of channel opening, and direct effects on GABAA (high doses)
C. Alcohol: Enhances actions of GABA at GABAA receptor
D. GABA channel blockers: picrotoxin
E. Etomidate and Propofol (Diprovan; aka “milk of amnesia”): beta2 and beta3 subunit containing receptors
F. Neurosteroids (e.g., progesterone and deoxycortisone) for treating depression, etc
Benzodiazepines: Chemistry and Metabolism
Structure Activity Relationships of Benzodiazepines:
1 Position alkylation –> source of active metabolites
2 Position NH2 or N(CH3)2 is active; oxo is active (i.e. valium)
3 Position has decreased activity; 3-OH rapid excretion
4-Nonoxide is active
Substitution on 5-phenyl has decreased activity
7 Position with an electronegative group is good
Annealating the 1-2 bond with an “electron rich” ring (triazole or imidazole) yields high affinity and decreased half-life
Metabolism of diazepam
long half-life
diazepam –> desmethyldiazepam –> oxazepam
BZDs with intermediate and rapid elimination rates
Intermediate: oxazepam, lorazepam
Rapid: alprazolam, triazolam
Benzodiazepines: PHARMACOKINETICS - slow
Slow Elimination Rates: All have active metabolites
Chlordiazepoxide (Librium®): 1st benzodiazepine, used as an anxiolytic and for alcohol withdrawal, accumulation of metabolites
Diazepam (Valium®)
– Prototypical benzodiazepine, used as an anxiolytic, for alcohol withdrawal, and for
treatment of convulsive disorders (seizures), accumulation of metabolites
Flurazepam (Dalmane®)
– Used as a hypnotic, accumulation of metabolites
Clorazepate (Tranxene®)
– Used as an anxiolytic, for alcohol withdrawal, and for treatment of convulsive disorders, accumulation of metabolites
Quazepam (Doral®)
– Used as a hypnotic, accumulation of metabolites (good or bad for helping sleeping?) - BAD
Prazepam (Currently unavailable in the US) - Used as an anxiolytic
Benzodiazepines: PHARMACOKINETICS - intermediate
Intermediate Elimination Rates:
Alprazolam (Xanax®)
– Withdrawal symptoms can present if abrupt discontinuation occurs, used as an anxiolytic and anesthetic
Lorazepam (Ativan®)
– Used as an anxiolytic and as a hypnotic
Clonazepam (Klonopin®)
– Tolerance may develop with prolonged use, used as an anticonvulsant
Oxazepam (Serax®)
– Used as an anxiolytic and for alcohol withdrawal
Temazepam (Restoril®)
– Used as a short-term hypnotic
Benzodiazepines: PHARMACOKINETICS - rapid
Rapid Elimination Rates:
Midazolam (Versed) – Rapid anesthesia
Triazolam (Halcion®, Discontinued) – Used as a short-term hypnotic
Benzodiazepines: Biotransformation and Therapeutics - slow elimination
Benzodiazepines usage:
Slow Elimination
– Accumulation
– Active Metabolites
– Drowsiness and Sedation
– Useful in patients who “wake up”
Benzodiazepines: Biotransformation and Therapeutics - intermediate to rapid elimination
Intermediate to Rapid Elimination
– Preferable in patients with hepatic problems – Preferable in elderly patients
– Drugs that alter liver enzymes
– Rapid tolerance
– Rebound Insomnia
Benzodiazepines: GENERAL CONSIDERATIONS
Readily absorbed (can delayed by food)
have active metabolites or are converted to active forms
Increased lipid solubility will increase speed of delivery to brain
Redistribution to highly perfused tissue may decrease duration of action
Cross placental barrier and are detected in breast milk
Extensive protein binding, but not clinically significant
Benzodiazepines: PHARMACOLOGICAL PROPERTIES
Anxiolytic
Sleep Physiology
– Reduce sleep latency
– Increase total sleep time
– Increase stage 2
– Decrease REM
– Decrease stage 3 and 4 (good or bad?)
– Tolerance and rebound to delta and REM
Anticonvulsant activity
Muscle relaxant
Cardiovascular and respiratory depression (major issue when combine with other agents)
Anterograde amnesia
Unable to recall events that occurred
Benzodiazepines: TOXICOLOGY
Side Effects –> dose dependent
– Sedation
§ Confusion
§ Ataxia
§ Daytime Sedation: With longer acting agents –> tolerance develops
– Weakness, Headache, Vertigo, Nausea, Paradoxical effects
Precautions and Interactions
– Other sedatives, Alcohol
– Pregnancy and breast-feeding
Drug Dependence and Abuse
– Abuse Potential –> Low vs barbiturates
– Small “Kick”: Often when in combination with other drugs of abuse
BENZODIAZEPINE ANTAGONIST
Flumazenil (Romazicon®)
Therapeutic use –> treat BZD overdose
Initial Dose
– 0.2 mg IV over 30 seconds
– If desired consciousness is not obtained, increase to 0.3 mg IV over 30 seconds
Max Total Cumulative Dose – 3 mg (usual range 1-3mg)
Side Effects
– Induce Convulsions
– Panic Attacks
– Agitation
– Confusion
– Nausea and Vomiting
– Headache
Non-benzodiazepines
Z-hypnotics: act at BZD binding site (BZ1 receptor)
zolpidem
zaleplon
eszopiclone
Zolpidem (ambien, ambien CR)
Short-term treatment of insomnia
– With difficulty of sleep-onset
– Ambien CRTM for sleep maintenance
Zaleplon (sonata)
Short-term treatment of insomnia (7-10 days) Rapid acting, Rapidly eliminated
Little tolerance or dependence
Eszopiclone (lunesta)
Active enantiomer of zopiclone
– 50 times greater affinity
Treatment of insomnia
– Approved for long-term use
“Z-Hypnotics” – Common Features
Metabolism
– CYP3A4 to some extent
Overdose Treatment
– Flumazenil (Romazicon®)
Side Effects
– Daytime drowsiness, dizziness, ataxia, nausea, and vomiting
– Cause less negative effects on sleep patterns vs. BZD
– Sleep-driving, sleep-cooking, sleep-eating, sleep-sex (FDA: warn your patient)
Illicit use of sedative-hypnotics that target the benzodiazepine binding site
Benzodiazepines
– Flunitrazepam (C-IV): Not Available in United States; “Roofies”; DEA recommends changing to C-I; Anterograde Amnesia – Dangerous aid for sexual assault (mainly combine with alcohol)
– Clonazepam (C-IV) (research use in treating social deficits of autism): Klonopin®
Nonbenzodiazepines
– Zolpidem (C-IV): Ambien® and Ambien CRTM; “A-minus” and “Zombie Pills”; Dangerous aid for sexual assault; Teen party drug
Barbiturates classifications - long acting
Anticonvulsants
– Phenobarbital (Luminal®)
– Mephobarbital (Mebaral®)
Barbiturates classifications - short to intermediate acting
Sedative-Hypnotics
– Amobarbital (Amytal®)
– Butabarbital (Butisol Sodium®)
– Pentobarbital (Nembutal®)
– Secobarbital (Seconal®)
– Aprobarbital (Alurate®)
Barbiturates classifications - ultra-short acting
IV Anesthetics
– Thiopental (Pentothal®)
– Methohexital (Brevital® Sodium)
– Thiamylal (Surital®)
Barbiturates: pharmacology
Sleep Physiology
– Comparable to BZD: Decrease REM; Slow Deep Sleep
Cardiovascular Depression –> at high doses
Respiratory depression –> death
Enzyme interactions: compete for cytochrome P450s for metabolism; enzyme induction
Anticonvulsant, idiosyncratic excitement and pain, dependance, tolerance, abuse, withdrawal, overdose, “after effect” - hangover, accumulation
Barbiturates: pharmacokinetics
Duration of Action
– Inversely proportional to lipid solubility
Decrease of Activities
– Metabolic transformations and redistribution
Ultra-Short and Short Acting
– Determined by redistribution
Anesthetics
– Determined by lipid solubility and rapid redistribution
Long Half-life
– Accumulation
Barbiturates
bind to all GABAA alpha1-5; Increase the duration of channel opening; and direct effects on GABAA channel (high doses); higher risk
Benzodiazepines
bind to all GABAA alpha1-5; Increase frequency of GABAA channel opening; medium risk
Z-hypnotics
bind to GABAA BZ1 receptors of alpha1; Increase frequency of GABAA channel opening; lower risk
