Pathophysiology of Anxiety and Sleep disorders Flashcards
what is a sedative
Calms anxiety, decreases excitement and activity, does not produce drowsiness, or impair performance
what is a Anxiolytic
Antianxiety, relieves anxiety without sleep or sedation (not all anxiolytics are sedatives
what is a Hypnotic
Induces sleep, implies restful, refreshing sleep, not “hypnotized!”, natural sleep (medial use term: sleeping-inducing)
what is a Narcotic
Actually means “sleep producing”, now refers to opioids or illegal drugs
What is the reticular formation
The reticular formation extends through the central core of the medulla oblongata pons and 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
What are the stages of sleep
Wakefulness
Non-rapid eye movement (NREM) slow-wave sleep
Rapid eye movement (REM) sleep
what is NREM sleep
NREM sleep
– Stage 1 (dozing)
– Stage 2 (unequivocal sleep)
– Stage 3 (voltage increase, frequency decrease)
– Stage 4 (delta waves
What factors 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”
what are the 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 structure
Pentameric structure comprised of 5 subunits from several polypeptide
classes
many subtypes a1, a2,a3,a5, bx, and yx
GABAA Receptor/Chloride Ion Channel Complex Targets for Sedative-Hypnotics
Orthosteric site: GABA (a1 and b2)
Allosteric Sites benzodiazepine (BZD) site (a1 and g2)
-Barbiturate
-Ethanol
-Glucocorticoid
Channel pore (picrotoxin)
Ligands Acting at the BZD Receptor
Benzodiazepines: Facilitate GABA action (e.g., a1-5), increase
frequency, require intact GABA system (internal safety system)
Non-Benzodiazepines (Z-Hypnotics): zolpidem (Ambien®), zaleplon (Sonata®), eszopiclone (LunestaTM) – BZ1 receptors of a1
BZD Antagonists: flumazenil (Romazicon®), overdose treatment
Inverse BZD Agonists: B carbolines
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”): b2 and b3 subunit containing receptors
F. Neurosteroids (e.g., progesterone and deoxycortisone)
for treating depression, etc
Structure Activity Relationships of Benzodiazepines:
1 Position alkylation source of active metabolites
Annealating the 1-2 bond with an “electron rich” ring (triazole or
imidazole) yields high affinity and decreased half-life
which drugs have a slow elimination rate (benzodiazepines)
Chlordiazepoxide (Librium®)
Diazepam (Valium®)
Flurazepam (Dalmane®)
Clorazepate (Tranxene®)
Quazepam (Doral®)
Prazepam (Currently unavailable in the US)
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?
Prazepam
(Currently unavailable in the US) Used as an anxiolytic
Drugs with Intermediate Elimination Rates?
Alprazolam (Xanax®)
Lorazepam (Ativan®)
Clonazepam (Klonopin®)
Oxazepam (Serax®)
Temazepam (Restoril®)
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
Rapid Elimination Rates drugs
Midazolam (Versed)
Triazolam (Halcion®, Discontinued)
Midazolam (Versed)
Rapid anesthesia
Triazolam (Halcion)
discontinued Used as a short-term hypnotic
Slow elimination benzos cause
accumulation active metabolites drowsiness and sedation useful in patients who wake up
intermediate to rapid benzos
Preferable in patients with hepatic problems
Preferable in elderly patients
Drugs that alter liver enzymes
Rapid tolerance
Rebound Insomnia
general considerations of benzos
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
Properties of Benzos
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
toxicology of benzos
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
What is a 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
* For who developed dependence
Zolpidem (Ambien®, Ambien CRTM)
Short-term treatment of insomnia
With difficulty of sleep-onset
Ambien CRTM for sleep maintenance
Ambien® and Ambien CRTM
“A-minus” and “Zombie Pills”
Dangerous aid for sexual assault
Teen party drug
Non-Benzodiazepines
Z-Hypnotics”: Act at BZD Binding Site (BZ1 receptor)
Zolpidem (Ambien®, Ambien CRTM)
Zaleplon (Sonata®)
Eszopiclone (LunestaTM)
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)
Zaleplon (Sonata®)
Short-term treatment of insomnia (7-10 days)
Rapid acting, Rapidly eliminated
Little tolerance or dependence
Eszopiclone (LunestaTM)
Active enantiomer of zopiclone
50 times greater affinity
Treatment of insomnia
Approved for long-term use
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®
long acting barbiturates
Anticonvulsants
– Phenobarbital (Luminal®)
– Mephobarbital (Mebaral®
Short to Intermediate Acting barbiturates
Sedative-Hypnotics
– Amobarbital (Amytal®)
– Butabarbital (Butisol Sodium®)
– Pentobarbital (Nembutal®)
– Secobarbital (Seconal®)
– Aprobarbital (Alurate®)
Ultra-Short Acting
IV Anesthetics
– Thiopental (Pentothal®)
– Methohexital (Brevital® Sodium)
– Thiamylal (Surital®)
Pharmacology of Barbiturates
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
Pharmacokinetics of Barbiturates
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
BZDvs BBT vs z-hypnotics
Barbiturtates (BBT): bind to all GABAA a1-5; Increase the duration of channel opening; and direct effects on GABAA channel (high doses); higher risk
Benzodiazepines (BZDs): bind to all GABAA a1-5; Increase frequency of GABAA channel opening; medium risk
Z-Hypnotics: bind to GABAA BZ1 receptors of a1; Increase
frequency of GABAA channel opening; lower risk
The use and limitation of Flumazenil
