Transcript No Slide Title

Drugs and Sleep
Developed at EVMS with NIH support to JC Ware (HL03652-04)
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The case of the
sleepless accountant
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Key Points
• Diagnosis, not complaint, should
determine treatment and medication
use.
• Hypnotic drugs do little to directly
enhance sleep. The major benefit is to
reduce arousal, therefore allowing sleep
to occur.
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FDA Recognized Hypnotics
• Benzodiazepines (BZ)
• Benzodiazepines - Like
• Non benzodiazepines
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A brief history from laudanum
to imidazopyridines
• Antiquity - Alcohol and laudanum (Example:
laudanum use by ship’s surgeon in Patrick
O’Brien’s seafaring novels)
• 1860s to ‘70s - Bromides and chloral
hydrate (key ingredient in a Mickey Finn)
• 1880s - Paraldedehyde, urethane,
sulfonal
• 1900s - Barbiturates (over 2500 synthesized)
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A brief history (cont.)
• 1960s - Benzodiazepines (3000+
synthesized), 1st marketed chlordiazepoxide (Librium)
• 1980s & 1990s - Imidazopyridines (eg,
zolpidem), cyclopyrrolones (eg, zopiclone,
in Europe since 1985)
• 2000s - Pyrazolopyrimidines (eg,
zaleplon)
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Pipeline Drugs
• (R) Zopiclone (being tested in US) may
increase deep sleep. Is there an
immune system connection?
• Neuroactive steroids
• BZ and BZ-like drugs
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Benzodiazepines (BZ)
Onset of
Action (Min)
Generic
Brand
½ life
Estazolam
Flurazepam
ProSom
Dalmane
15 - 30
15 - 30
interm
long
Quazepam
Temazepam
Doral
Restoril
15 - 30
45 – 60
long
interm
(H2O rather than lipid soluble)
Triazolam
Halcion
15 - 30
short
(sublingual administration possible)*
*Kroboth et al. Triazolam pharmacokinetics after intravenous, oral, and sublingual administration. J Clin
Psychopharmacol 1995;15:259-262.
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Benzodiazepines - Like
(nonBZ but mediated through GABA receptors)
Generic
Zolpidem
Brand
Ambien
Onset of
Action (Min)
15 - 30
½ life
Short
(Curent best seller. Among the most
expensive. Little insomnia rebound at
10 mg when used for 1 month or less.)
Zaleplon
Sonata
15 - 30
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Some Non-benzodiazepines
(oldies and less safe than BZ)
Chloral Hydrate Triclos
Has pediatric use
Why?
Ethchlorvynol
Placidyl
No reason to use
Pentobarbital
Nembutal No reason to use
Secobarbital
Seconal
No reason to use
Glutethimide
Doriden
No reason to use
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Other Non-BZ
Thalidomide
Now AIDS, leprosy &
aphthous ulcer use.
Why? Sleep effects?
Hydroxyzine
(Atarax, Vistaril)
Sedation probably
through H1 effects
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Over-The-Counter-Drug
Dimenhydrinate (Draminine): OTC most
commonly used by elderly
Diphenhydramine: May increase AM
drowsiness more than prescription
hypnotic and may be less
efficacious; but, no definitive and
unconfounded studies
Diphenhydramine & Acetaminophen
(Excedrin P.M., Tylenol PM, Unisom)
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Anxiolytics versus Hypnotics:
What is the difference?
• Primarily a marketing decision
• Time of administration
• Dose
• Research / Development: Objective
measures of efficacy?
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Potential Adverse Events
Can a sleeping pill cause or facilitate:
• Murder?
• Date rape?
The case of the 70 year old housewife
with baseball watching husband.
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Potential Adverse Events
• Anterograde amnesia (case of the
Californian giving a New York lecture)
• Masking of untreated problem
• Daytime sedation
• Rebound insomnia & anxiety
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Potential Adverse Events
• Disinhibition (dancing on the piano with
a lampshade over ones head)
• Tolerance & dependence
• Distortion of normal sleep
• Cognitive & psychomotor impairment
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Ten most frequently used drugs
to treat insomnia 1987-1996
Drug (cost factor)
Approved Conditions
Alprazolam (1)
Anxiety / panic
Amitriptyline (1)
Depression / pain
Clonazepam (1.1)
Seizures / PLMS /
neuralgia
Doxepin (1.3)
Depression / anxiety
Flurazepam (1.7)
Insomnia
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Ten most frequently used drugs
to treat insomnia 1987-1996
Drug (cost factor)
Approved Conditions
Lorazepam (2.6)
Anxiety/ insomnia
Temazepam (1.5)
Insomnia
Trazodone (1.4)
Depression
Triazolam (3.0)
Insomnia
Zolpidem (10.9)
Insomnia
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Pipeline Hypnotics
Substance p antagonists: Effects are
apparently independent of GABA
system
Neuroactive steroids: Apparently GABA
mediated effects
(S)Zopiclone: At least in part GABA
mediated (does it increase deep
sleep?)
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The Health Food Store
L-Tryptophan: Taken off market because
of eosinophilia myalgia
Melatonin: Increases daytime sleepiness
during day but not an effective
hypnotic. Helps reset circadian
rhythm, but light overwhelms any
circadian rhythm setting effects. May
be proconvulsant in children. Birth
control pill in large doses?
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The Health Food Store (cont)
Valerian: Sedating effects may be
mediated through the GABA system.
Herbs & teas: Soothing warmth, placebo,
pre-sleep ritual, little objective data.
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Sedating Antidepressants
Amitriptyline: Anticholinergic, sedating,
strong REM sleep suppression.
Lethal over dose effects. Why?
Doxepin: Anticholinergic, sedating,
moderate REM suppression. Lethal
overdose effects. Why?
Mirtazapine: Newest with least PSG data
so far
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Sedating Antidepressants
Trazodone: Little anticholinergic effect.
Similar hypnotic effect to zolpidem
(50 mg = ~ 10 mg zolpidem).
Priapism (~1/10,000)
Trimipramine: May normalize sleep in
depressed patients. No REM
suppression. Anticholinergic
activity!
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Sedating antidepressants (Effective
substitutes for hypnotics? Yes, but . . . )
Anticholinergic activity increases successful
suicide rate with overdose in part by slowing
conduction in heart.
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Alerting Antidepressants
Protriptyline: Anticholinergic, strong REM
sleep suppression
Bupropion: No REM sleep suppression.
No / little anticholinergic activity
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Properties to Consider
Absorption: Should be quickly absorbed
for rapid onset
Cost: Varies by more than 10 fold.
Half-life (metabolism and elimination):
Should have intermediate to short
half-life
Metabolites: May be problematic due to
half life and drug interactions
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Properties to Consider
Drug interactions: Occur with many CNS
drugs and may be mediated by the
cytochrome P450 system.
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Some Drugs Metabolized by
Cytochrome P-450 Enzyme P3A4
Antidepressants
Sedative-hypnotics
Nefazodone
alprazolam
Sertraline
clonazepam
Venlafaxine
diazepam
triazolam
zolpidem
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Examples of Effects Mediated by
the cytochrome P450 system
• Rifampin increases production of
CYP3A4 and negates benefit of
triazolam
• Diltiazem inhibits CYP3A4 and
increases potency of triazolam
(caffeine is metabolized by 1A2)
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Non Hypnotic “Hypnotics”
Examples
Analgesics: Improve sleep disturbed by
pain
Antidepressants: Improve sleep
disturbed by depression
Finasteride: Improves sleep disturbed by
nocturia
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Non Hypnotic “Hypnotics” (cont)
Examples
GERD medications: Improve sleep
disturbed by reflux
Sinemet (carbidopa-levodopa): Improves
sleep disturbed by Restless Leg
Syndrome
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Behavioral Techniques
Sleep Hygiene: Should have information
in office for patients
Sleep Restriction: Reduce (titrate) time in
bed to time patient can sleep
Cognitive Therapy: Deals with beliefs
concerning disturbed sleep
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Behavioral Techniques (cont)
Stimulus Control: Reduces arousal to
bedtime stimuli
Relaxation: May work only if excessive
tension
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Use a Hypnotic for the Following?
Why or Why Not?
• 47 year old healthy business man on
trip to Paris?
• 55 year old patient’s mother dies?
• 23 year old medical student on hs dose
of theophylline for asthma?
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Use a Hypnotic for the Following?
Why or Why Not? (cont)
• 57 year old healthy female with sleep
onset insomnia?
• 60 year old obese male with frequent
brief awakening?
• Ventilation: Continuos infusion of
sedation medication so patient doesn’t
pull out tube?
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Hints for Hypnotic Use
• Hx & P with dx should precede
treatment. Dx should not be “insomnia”
• All patients need sleep hygiene
education & follow-up
• Treat medical problems that may
disturb sleep, e.g., GERD
• Screen for depression screen (e.g.,
Beck)
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Hints for Hypnotic Use (cont)
• Does disturbed sleep affect quality of
life? If not, don’t treat with hypnotic
• Judicious short-term use of short acting
hypnotic in selected cases is OK
• Don’t mistake drug induced insomnia
rebound as evidence for continuing
need for medication
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Question 1
The half-life of a hypnotic medication is
most likely to effect:
a. Daytime sedation
b. Drug absorption
c. Hypnotic efficacy
d. Plasma level
e. Tolerance
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Question 2
A BZ may help to reduce typical sleep
walking because of its effects on
a. Deep sleep (stages 3 & 4)
b. REM sleep
c. Seizure threshold
d. Muscle tone
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Question 3
When using an anxiolytic to help sleep, it is
usually:
a. Given at a larger dose than when used to
treat anxiety
b. Given during the day to reduce the build
up of anxiety that may disturb sleep
c. Less likely to cause the most common
side effects associated with hypnotic
medications
d. It is more likely to suppress REM and
deep sleep than a hypnotic medication
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Question 4
Anterograde amnesia:
a. Is more likely to be noticed when using a
long acting hypnotic
b. Occurs only with a subgroup of
sedative/hypnotic medications
c. May affect memory for events before
taking the medication without affecting
performance
d. Is a good reason for on-call physicians
not to use a hypnotic medication
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Question 5
Melatonin:
a. Suppresses gonadotropins
b. Has its peak secretion soon after
sunrise
c. Caused marked sleepiness in a
study when given in a large dose
for birth control
d. May help phase delay the circadian
rhythm when given before bed
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Answers
1–d
2–a
3–a
4–d
5–a
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