PHRM845 Exam 4 Flashcards
Pathophysiology of anxiety and sleep disorders
What is a sedative?
Calms anxiety, decreases excitement and activity, does not produce drowsiness, or impair performance
What is an 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 and where is it located?
-An intricate system composed of loosely clustered neurons in what is otherwise white matter
-The reticular formation extends through the central core of the medulla oblongata, pons, and midbrain.
-It is very complex; contains dopamine, adrenergic, serotonergic, and cholinergic neurons
-Regulates sleep-wake transitions and synchronization of EEG.
Stages of sleep
-Wakefulness
-Non-rapid eye movement (NREM) slow-wave sleep
-Rapid eye movement (REM) sleep
NREM sleep stages
Stage 1 (dozing)
Stage 2 (unequivocal sleep)
Stage 3 (voltage increase, frequency decrease)
Stage 4 (delta waves)
EEG for REM sleep is similar to EEG when ___
Awake
Sleep deprivation means a decrease in time in ___
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”
How long is an Ultradian Rhythm?
90 minutes
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
What neurotransmitter is the main target for current medications?
GABA
What is GABA?
Major inhibitory signal that quiets the brain down.
Explain impact of GABA in seizures and anxiety
Seizure-too much excitability (not enough GABA)
Anxiety-want to quiet excitatory neurons
With GABA-A receptors, we want more ___ influx.
Cl-; chloride channel causes more negative charge and membrane becomes hyperpolarized making it harder to activate an action potential.
How do benzodiazepines bind to GABA-A receptor?
They bind at an allosteric binding site to allow more Cl- to enter.
GABA-A receptor/chloride ion channel complex is a target for
Sedative-hypnotics
Most common CNS GABA-A receptors
2a1, 2b2, 1g2
Orthosteric and allosteric sites on GABA-A receptor
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
Benzodiazepines are (very/not very) specific. They are also (addictive/not addictive).
Not very specific
Addictive because it binds so many different targets.
Z-hypnotics have (more/less) side effects because binding is very (specific/non-specific).
Less
specific
Modulation of the GABA-A receptor
a. BZD
b. Barbiturates
c. Alcohol
d. GABA channel blockers
e. Etomidate and propofol
f. Neurosteroids
BZDs: Increase frequency of channel opening,
Barbiturtates (Bbt): Increase duration of channel opening, and direct effects on GABAA (high doses)
Alcohol: Enhances actions of GABA at GABAA receptor
GABA channel blockers: picrotoxin
Etomidate and Propofol (Diprovan; aka “milk of amnesia”): b2 and b3 subunit containing receptors
Neurosteroids (e.g., progesterone and deoxycortisone) for treating depression, etc
Importance of GABA channel blocker: Picrotoxin
Toxic, so don’t use as a drug.
Directly blocks ion conduction pathway,
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
Half-life of diazepam
Long
Use of Chlordiazepoxide (Librium®)
1st benzodiazepine, used as an anxiolytic and for alcohol withdrawal, accumulation of metabolites
Use of Diazepam (Valium®)
Prototypical benzodiazepine, used as an anxiolytic, for alcohol withdrawal, and for treatment of convulsive disorders (seizures), accumulation of metabolites
Use of Flurazepam (Dalmane®)
Used as a hypnotic, accumulation of metabolites
Use of Clorazepate (Tranxene®)
Used as an anxiolytic, for alcohol withdrawal, and for treatment of convulsive disorders, accumulation of metabolites
Use of Quazepam (Doral®)
Used as a hypnotic, accumulation of metabolites (good or bad for helping sleeping?)
Use of Prazepam (Currently unavailable in the US)
Used as an anxiolytic
Meds with slow elimination rates: all have active metabolites
Chlordiazepoxide (Librium®)
Diazepam (Valium®)
Flurazepam (Dalmane®)
Clorazepate (Tranxene®)
Quazepam (Doral®)
Prazepam
Meds with intermediate elimination rates
Alprazolam
Lorazepam
Clonazepam
Oxazepam
Temazepam
Use of Alprazolam (Xanax®)
Withdrawal symptoms can present if abrupt discontinuation occurs, used as an anxiolytic and anesthetic
Use of Lorazepam (Ativan®)
Used as an anxiolytic and as a hypnotic
Use of Clonazepam (Klonopin®)
Tolerance may develop with prolonged use, used as an anticonvulsant
Use of Oxazepam (Serax®)
Used as an anxiolytic and for alcohol withdrawal
Use of Temazepam (Restoril®)
Used as a short-term hypnotic
Meds with rapid elimination rates
Midazolam and Triazolam
Use of Midazolam (Versed)
Rapid anesthesia
Importance of rapid elimination rates
Get in fast–>do job–>get out
**Good for seizures
Benzodiazepines usage
Slow Elimination
-Accumulation
-Active Metabolites
-Drowsiness and Sedation
-Useful in patients who “wake up”
Intermediate to Rapid Elimination
-Preferable in patients with hepatic problems
-Preferable in elderly patients
-Drugs that alter liver enzymes
-Rapid tolerance
-Rebound Insomnia
Which meds should we be careful with in elderly patients and why?
Benzodiazepines
Increase risk of falls, mobility, driving, and increase cognitive issues.
General considerations for benzodiazepines
-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
Are barbituates or benzodiazepines more dangerous?
Barbituates; as you increase the dose, you just keep increasing the side effects
-If you keep increasing the dose, it can lead to sedation; if increasing it more, it can cause seizure–>coma
-In a coma, the brain does not have much activity (“brain dead”) and many cannot wake up
-Increases frequency of Cl- opening and too many Cl- influx.
Is it easy or hard to OD on benzodiazepines?
Hard; easy on barbiturates
Pharmacological properties of benzodiazepines
-Anxiolytic
-Sleep Physiology
-Reduce sleep latency
-Increase total sleep time
-Increase stage 2
-Decrease REM
-Decrease stage 3 and 4 (good or bad?)–bad because you still feel like you did not get enough sleep
-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
**Not as commonly used as sleeping agents as before
**You increase total sleeping time, but decrease amount of time in REM
Toxicology of benzodiazepines
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)
**Does not lead to coma
**Often OD from multiple agents
**Alcohol also acts on GABA receptor, so pt can get pleasure from EtOH and BZD
BENZODIAZEPINE ANTAGONIST
Flumazenil (Romazicon®)
-Therapeutic use–>treat BZD overdose
Side Effects
-Induce Convulsions*
-Panic Attacks*
-Agitation
-Confusion
-Nausea and Vomiting
-Headache
*are for those who developed dependence
Is flumazenil a barbituate antagonist?
NO
Non-Benzos (Z-Hypnotics): act as a BZD binding site
-BZ1 receptor
Examples of Z-hypnotics
Zolpidem (Ambien®, Ambien CRTM)
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 (LunestaTM)
Active enantiomer of zopiclone
50 times greater affinity
Treatment of insomnia
Approved for long-term use
**These have a very specific binding
**Some take zolpidem (short term) version for longer time, but not great practice
Common features of Z-hypnotics
-Metabolism
-OD tx
Metabolism
CYP3A4 to some extent
Overdose Treatment
Flumazenil (Romazicon®)
Z-hypnotics 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 Long acting
Anticonvulsants
-Phenobarbital (Luminal®)
-Mephobarbital (Mebaral®)
Barbiturates short to intermediate acting
Sedative-Hypnotics
-Amobarbital (Amytal®)
-Butabarbital (Butisol Sodium®)
-Pentobarbital (Nembutal®)
-Secobarbital (Seconal®)
-Aprobarbital (Alurate®)
Barbiturates ultra-short acting
IV Anesthetics
-Thiopental (Pentothal®)
-Methohexital (Brevital® Sodium)
-Thiamylal (Surital®)
Pharmacology of barbiturates
-Anticonvulsant
-Idiosyncratic excitement and pain
-Dependence
-Tolerance
-Abuse
-Withdrawal
-Overdose
-“After Effect” (Hangover, Accumulation)
-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
PK 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
Summary of BZD and barbiturates
-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
**Flumazenil is used for BZD and Z-hypnotic OD
**Flumazenil cannot be used for barbiturate OD
-New GABA drugs are being tested to treat a variety of conditions and target different subunits.
-Depression, autism (excitation/inhibition imbalance)–>ketamine is the most effective drug for depression
-GABAA, GABAB
