Sedatives Flashcards
What NT mediate NREM sleep
GABA
Adenosine
What regulates REM sleep
Cholinergic cells turn REM on
Noradrenergic cells turn REM off
What facilitates arousal and wakefulness
Ascending reticular activating system and posterior hypothalamus
-NE, ACh, histamine, Substance P, corticotropin releasing factor
What is dopamine’s effect on sleep
Dopamine is alerting!
Low dopamine promotes sleepiness
What are important sleep wake concepts
Young adults have difficulty falling asleep
Middle aged and elderly have trouble staying asleep
Those with insomnia often also have anxiety, depression, or substance abuse disorders- and use nonRx drugs or alcohol to treat (esp. chronic insomnia)
Transient insomnia may be 2/2
Separation
Death in family
Job change
College exams
Common etiologies of insomnia are
Situational
Medical: CV, respiratory, chronic pain, endocrine, GI, Neuro, pregnancy
Psych
Pharm induced: anticonvulsants, central adrenergic blockers, diuretics, SSRI, steroids, stimulants
Goals of treating insomnia are
Correct underlying sleep complaint
Consolidate sleep
Improve daytime fxn
Avoid ADE from select therapies
What stimulus control procedures can you attempt as non-pharm Tx of insomnia
Establish regular times to wake up and go to sleep
Sleep only as much as you need to feel rested
Go to bed only when sleepy, no reading or TV in bed
Avoid trying to force sleep
Avoid blue-spectrum light
Avoid daytime naps
Schedule worry time during the day
What are sleep hygiene recommendations
Exercise 3-4x week, not close to bedtime
Create comfortable sleep environment (avoid temp extremes, loud noises, and light)
D/c alcohol, nicotine, and caffeine
Avoid large quantity of beverage at night
Do something relaxing you enjoy before bed
What effect do sedatives have
Reduce anxiety and exert calming effect; Take lowest dose possible to minimize degree of CNS depression
What effect do hypnotics have
Produce drowsiness and encourage onset and maintenance of state of sleep
More pronounced CNS depression than sedatives
What are sedatives and hypnotics used for
*Relief of anxiety and insomnia
sedation and amnesia for surgical procedures
Tx epilepsy and seizures
*Control of ethanol or other withdrawal states
Muscle relaxation in some neuromuscular d/o
Diagnostic aids or Tx in psych
What is the good thing about benzos vs barbituates and alcohol
Benzos will typically level off at a level of anesthesia as the dose increases
Barbituates and alcohol can send you into a coma
What are the PK of sedatives and hypnotics
Absorption/Distribution: Lipid soluble, absorbed from GI tract, good distribution to brain
Metabolism/Excretion: metabolized before elimination by hepatic enzymes.
What are the MC used drugs for insomnia
Eszopiclone, Zaleplon, Zolpidem (new, non-benzo GABA agonists; sedatives only)
Estazolam, Flurazepam, Quazepam, Temazepam, Triazolam (benzos; sedative, anxiolytic, muscle relaxer, anti-convulsant)
What is the MOA of benzos
Benzo receptor is in the thalamus, limbic structures, and cerebral cortex
Binding their receptor facilitates GABA in creating inhibition
Benzos are used for
acute anxiety panic attack GAD insomnia skeletal muscle relaxer seizure disorder
PK of benzos is
Hepatic metabolism
Active metabolites
CNS depression
2-4 hr half life
Benzo toxicity can lead to
Extension of CNS depressant actions
Tolerance
Dependence
Which benzos do NOT have active metabolites
Lorazepam
Oxazepam
Zolpidem
ADE of benzos are
high dose: daytime sedation, psychomotor incoordination, cognitive deficit, prolonged half life in elderly
Tolerance over time
Anterograde amnesia (no memory after taking dose)
Rebound insomnia after abrupt d/c
-take lowest dose possible to min rebound insomnia and amnesia
How long do most benzos maintain hypnotic efficacy
1 month
FDA requires this warning label on benzos AND barbiturates
Caution regarding anaphylaxis, facial angioedema, complex sleep behaviors
What substances interact with benzos MC
Alcohol Antihistamines Antipsychotics Opioid analgesics TCA
OD on benzos can cause
Potentially lethal respiratory and CV depression; more likely w/ alcohol, barbs, and carbamates; less common with new agents like zolpidem
What can reverse the CNS depressant effects of benzos
Flumazenil!
but no benefit on OD of other sedatives or hypnotics
How does Flumazenil work
Antagonist at benzo receptor site on GABA receptor (aka bring you up!)
IV but short half life
Toxicities of flumazenil ae
agitation
confusion
possible withdrawal syndrome
How do newer hypnotics work (zolpidem, zaleplon, eszopiclone)
they exert CNS effects via interaction w/ BZ1 or W1 benzo receptors.
They bind more selectively than benzos and bind only a1 GABA subunit near the benzo site (also facilitate Cl channel opening)
They are not benzos, but flumazenil still works on them
May cause dependence
What are the barbiturates
Amobarbital Butabarbital Pentobarbital Phenobarbital Secobarbital Thiopental
How do barbiturates work
Facilitate and promote inhibitory effect of GABA and glycine- binds to different site than benzos
May also block excitatory glutamic acid and sodium channels
Flumazenil does NOT work on them
Barbiturates are used for
Anesthesia (thiopental)
Insomnia and sedation (secobarbital)
Seizure d/o (phenobarbital)
What is the PK of barbiturates
Oral activity
Hepatic metabolism
Induce metabolism of many drugs
4-6o hr half life
Toxicities of barbiturates are
CNS depressant actions
tolerance
high dependence
What effect do baribturates and carbamates have on the liver
induce liver enzymes= cause drug interactions
Precipitate acute intermittent porphyria
Chloral hydrate can increase anticoag effect
What is the role of antihistamines in sedation
They have sedating properties and are usually effective in treating mild insomnia
Diphenhydramine and Doxylamine preferred
But, tolerance can develop, and increasing does does not produce a linear effect.
ADE of antihistamines are
anticholinergic ADE!
blind, dry, red, hot
How do antidepressants work in sedation
Amitriptyline, Doxepin, and Nortriptyline are sedating antidepressants that induce sleep continuity
*Low dose doxepin is FDA approved for insomnia
Mirtazapine promotes sleep
Trazodone improves sleep continuity at bedtime
ADE of antidepressants are
daytime sedation
anticholinergic ADE
Mirtazapine: also weight gain
Trazodone: carryover sedation, a-adrenergic block (orthostais, worse in elderly), priapism
Who is Trazodone good for
Those prone to substance abuse- does not cause dependence
Those with SSRI and buproprion induced insomnia
What is Suvorexant
recently approved dual Orexin A and B receptor antagonist
Instead of inducing sleepiness, it turns off the wake signaling! Taken at bedtime
What is orexin (hypocretin)
Excitatory action on 5-HT, histamine, ACh, and DA
Facilitatory role on GABA and glutamate induced neurotransmission
Has a primary role in sleep and arousal; energy regulation
MC ADE of Suvorexant are
Somnolence
Sleep paralysis, cataplexy, other narcolepsy-like Sx
What is Ramelteon
Melatonin receptor agonist approved for sleep-onset insomnia
Selective MT1 and 2 receptor to help melatonin regulate circadian rhythm and sleep onset
-Forms active metabolite via CYP1A2
What are ADE of ramelteon
HA, dizziness, and somnolence
Who is Ramelteon good for
Those with hx of substance abuse- not a controlled substance!
Those w/ COPD and sleep apnea
What is Valerian
Herb with sedative-hypnotic properties for those w/ insomnia (can drink as tea at bedtime)
MOA may involve increasing GABA, but not fully known
-bad? it smells like gym socks
What drugs do you do in different states
Anxiety: Alprazolam, Clonazepam
Sleep d/o: Estazolam, Flurazepam, Triazolam, Zolpidem, Zaleplon, Eszopiclone
Induce anesthesia: Thiopental
Component of anesthesia: diazepam, midazolam
Seizure d/o: Clonazepam, phenobarbital
Bipolar: Clonazepam
Muscle spasticity: diazepam
Managing withdrawal (longer acting): Chlordiazepoxide*, diazepam
What do you need in order to diagnose anxiety disorder
overt anxiety or overt manifestation of a copine mechanism
Not just an adjustment disorder
Somatic Sx (dyspnea, palpitations, paresthesias)
Not 2/2 physical disorder or psych condition or drug abuse
What medical illnesses are associated with anxiety
Cardiovascular: angina, arrhythmia, CHF, HTN
Endocrine: cushings, DM, hyper/hypothyroid, hypoglycemia
GI: IBS, IBD, PUD
Neuro: migraine, Sz, stroke
Resp: asthma, COPD, PE, PNA
anemia, cancer, SLE
What are some drug classes associated with anxiety Sx
anticonvulsants antidepressants antiHTN antibiotics bronchodilators corticosteroids dopamine agonists herbals ecstasy, marijuana NSAIDs caffeine, cocaine, amphetamines, nicotine Sympathomimetics thyroid hormones
What is first line for GAD
Duloxetine Escitalopram Paroxetine Sertraline Venlafaxine
What is first line for panic disorder
SSRI
Venlafaxine
What is first line for social anxiety disorder
Escitalopram Fluvoxamine Paroxetine Sertraline Venlafaxine
What is Buspirone
a selective anxiolytic; Partial 5HT agonist +/- D2 agonist Partial 5HT1a agonist Minimal CNS depressant effects; can still drive while on it No anticonvulsant or muscle relaxant properties Safe in pregnancy! Minimal dependence with long term use Little rebound anxiety
PK of Buspirone are
Slow onset (1 week)
Forms active metabolite
Interacts with CYP3A4 inducer and inhibitor
Who is Buspirone good for
Generalized anxety disorder
Less effective for panis disorder
ADE of Buspirone are
GI distress
tachycardia
paresthesia
What drugs treat panic disorder (specifically)
SSRI: Citalopram, Escitalopram, Fluoxetine, Fluvoxatine, Paroxetine, Sertraline
SNRI: Venlafaxine
Benzo: Alprazolam, Clonazepam, Diazepam, Lorazepam
TCA: Imipramine
MOI: Phenelzine
What type of alprazolam is best for panic disorder
Xanax XR! it has a longer half life so you dont get panic Sx when you stop taking it like you do with regular xanax
