Drugs and Sleep
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Transcript of Drugs and Sleep
Drugs and Sleep
Developed at EVMS with NIH support to JC Ware (HL03652-04) Sleep Academic Award 1
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The case of thesleepless 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
Benzodiazepines (BZ) Onset of
Generic Brand Action (Min) ½ life
Estazolam ProSom 15 - 30 interm
Flurazepam Dalmane 15 - 30longQuazepam Doral 15 - 30 longTemazepam Restoril 45 – 60 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)
Onset ofGeneric Brand Action (Min)
½ life
Zolpidem Ambien 15 - 30 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 Ultra short
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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 NembutalNo 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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Can a sleeping pill cause or facilitate:
•Murder?
•Date rape?
The case of the 70 year old housewife with baseball watching husband.
Potential Adverse Events
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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 sedationb. Drug absorptionc. Hypnotic efficacyd. Plasma levele. 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 sleepc. Seizure thresholdd. 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 hypnoticb. Occurs only with a subgroup of
sedative/hypnotic medicationsc. May affect memory for events before
taking the medication without affecting performanced. Is a good reason for on-call physicians
not to use a hypnotic medication
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Question 5
Melatonin:a. Suppresses gonadotropinsb. Has its peak secretion soon after
sunrisec. Caused marked sleepiness in a
study when given in a large dose for birth controld. 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