Pathophysiology of Anxiety and Sleep disorders Flashcards by Brianna Lent

what is a sedative

Calms anxiety, decreases excitement and activity, does not produce drowsiness, or impair performance

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what is a Anxiolytic

Antianxiety, relieves anxiety without sleep or sedation (not all anxiolytics are sedatives

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what is a Hypnotic

Induces sleep, implies restful, refreshing sleep, not “hypnotized!”, natural sleep (medial use term: sleeping-inducing)

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what is a Narcotic

Actually means “sleep producing”, now refers to opioids or illegal drugs

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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

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What are the stages of sleep

Wakefulness
Non-rapid eye movement (NREM) slow-wave sleep
Rapid eye movement (REM) sleep

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what is NREM sleep

NREM sleep
– Stage 1 (dozing)
– Stage 2 (unequivocal sleep)
– Stage 3 (voltage increase, frequency decrease)
– Stage 4 (delta waves

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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”

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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

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GABAergic Neurotransmission

GABAA Receptors
GABAB Receptors
GABA Transporters (GAT-1)
GABA-T (Transaminase)

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GABAa receptor structure

Pentameric structure comprised of 5 subunits from several polypeptide
classes
many subtypes a1, a2,a3,a5, bx, and yx

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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)

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Ligands Acting at the BZD Receptor

Benzodiazepines: Facilitate GABA action (e.g., a1-5), increase
frequency
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

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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

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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

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which drugs have a slow elimination rate (benzodiazepines)

Chlordiazepoxide (Librium®)
Diazepam (Valium®)
Flurazepam (Dalmane®)
Clorazepate (Tranxene®)
Quazepam (Doral®)
Prazepam (Currently unavailable in the US)

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Chlordiazepoxide (Librium®)

1st benzodiazepine, used as an anxiolytic and for alcohol withdrawal, accumulation of
metabolites

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Diazepam (Valium®)

Prototypical benzodiazepine, used as an anxiolytic, for alcohol withdrawal, and for
treatment of convulsive disorders (seizures), accumulation of metabolites

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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

slow elimination (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

Properties of Benzos

Anxiolytic Sleep Physiology: 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®) treat BZD overdose 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

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

illicit use of Benzos

flunitrazepam and clonazepam and zolpidem

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