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Drugs and Sleep

Drugs and Sleep. Developed at EVMS with NIH support to JC Ware (HL03652-04). Sleep Academic Award 1. The case of the sleepless accountant. Key Points. Diagnosis, not complaint, should determine treatment and medication use.

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Drugs and Sleep

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  1. Drugs and Sleep Developed at EVMS with NIH support to JC Ware (HL03652-04) Sleep Academic Award 1

  2. The case of thesleepless accountant Sleep Academic Award 2

  3. 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. Sleep Academic Award 3

  4. FDA Recognized Hypnotics Benzodiazepines (BZ) Benzodiazepines - Like Non benzodiazepines Sleep Academic Award 4

  5. 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) Sleep Academic Award 5

  6. 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) Sleep Academic Award 6

  7. 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 Sleep Academic Award 7

  8. Benzodiazepines (BZ) Onset of Generic Brand Action (Min)½ life Estazolam ProSom 15 - 30 interm Flurazepam Dalmane 15 - 30 long Quazepam Doral 15 - 30 long Temazepam 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. Sleep Academic Award 8

  9. Benzodiazepines - Like (nonBZ but mediated through GABA receptors) Onset of Generic Brand Action (Min)½ life Zolpidem Ambien 15 - 30 Short (Curent best seller. Among the most expensive. Little insomnia rebound at 10 mgwhen used for 1 month or less.) Zaleplon Sonata 15 - 30 Ultra short Sleep Academic Award 9

  10. 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 Sleep Academic Award 10

  11. Other Non-BZ Thalidomide Now AIDS, leprosy & aphthous ulcer use. Why? Sleep effects? Hydroxyzine (Atarax, Vistaril) Sedation probably through H1 effects Sleep Academic Award 11

  12. 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) Sleep Academic Award 12

  13. Anxiolytics versus Hypnotics: What is the difference? • Primarily a marketing decision • Time of administration • Dose • Research / Development: Objective measures of efficacy? Sleep Academic Award 13

  14. 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. Sleep Academic Award 14

  15. Potential Adverse Events • Anterograde amnesia (case of the Californian giving a New York lecture) • Masking of untreated problem • Daytime sedation • Rebound insomnia & anxiety Sleep Academic Award 15

  16. Potential Adverse Events • Disinhibition (dancing on the piano with a lampshade over ones head) • Tolerance & dependence • Distortion of normal sleep • Cognitive & psychomotor impairment Sleep Academic Award 16

  17. 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 Sleep Academic Award 17

  18. 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 Sleep Academic Award 18

  19. 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?) Sleep Academic Award 19

  20. 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? Sleep Academic Award 20

  21. 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. Sleep Academic Award 21

  22. 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 Sleep Academic Award 22

  23. 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! Sleep Academic Award 23

  24. Sedating antidepressants (Effective substitutes for hypnotics? Yes, but . . . ) Anticholinergic activity increases successful suicide rate with overdose in part by slowing conduction in heart. Sleep Academic Award 24

  25. AlertingAntidepressants Protriptyline: Anticholinergic, strong REM sleep suppression Bupropion: No REM sleep suppression. No / little anticholinergic activity Sleep Academic Award 25

  26. 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 Sleep Academic Award 26

  27. Properties to Consider Drug interactions: Occur with many CNS drugs and may be mediated by the cytochrome P450 system. Sleep Academic Award 27

  28. Some Drugs Metabolized by Cytochrome P-450 Enzyme P3A4 Sleep Academic Award 28

  29. 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) Sleep Academic Award 29

  30. Non Hypnotic “Hypnotics” Examples Analgesics: Improve sleep disturbed by pain Antidepressants: Improve sleep disturbed by depression Finasteride: Improves sleep disturbed by nocturia Sleep Academic Award 30

  31. Non Hypnotic “Hypnotics” (cont) Examples GERD medications: Improve sleep disturbed by reflux Sinemet (carbidopa-levodopa): Improves sleep disturbed by Restless Leg Syndrome Sleep Academic Award 31

  32. 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 Sleep Academic Award 32

  33. Behavioral Techniques (cont) Stimulus Control: Reduces arousal to bedtime stimuli Relaxation: May work only if excessive tension Sleep Academic Award 33

  34. 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? Sleep Academic Award 34

  35. 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? Sleep Academic Award 35

  36. 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) Sleep Academic Award 36

  37. 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 Sleep Academic Award 37

  38. 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 Sleep Academic Award 38

  39. 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 Sleep Academic Award 39

  40. 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 Sleep Academic Award 40

  41. 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 Sleep Academic Award 41

  42. 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 Sleep Academic Award 42

  43. Answers 1 – d 2 – a 3 – a 4 – d 5 – a Sleep Academic Award 43

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