1. Effects of Drugs on PSG and Sleep
Rochelle Zozula, Ph.D., DABSM
Sleep Services International, LLC
Clinical Assoc. Professor of Neuroscience, Seton Hall University, School of Health & Medical Sciences

2. © 1987 Partnership for a Drug-free America

3. Drugs and Sleep
Daytime drowsiness or nocturnal insomnia may be due to :
Direct pharmacologic effect
Disturbance in sleep patterns
Insomnia or nightmares
Aggravation of sleep disorder
Sleep apnea, restless leg syndrome
Drug withdrawal

4. General Rules Stage N1 Stage N3 (SWS) Stage REM
Increase can lead to increased arousals or wakefulness
Stage N3 (SWS)
Decrease can lead to feelings of not being well rested and muscle aches
Stage REM
Decrease may lead to parasomnias
Increase may lead to nightmares

5. General Rules
One neurotransmitter/neuromodulator may involve multiple mechanisms.
The effect of the drug may vary depending on dosage and method of administration.
Many pharmacologic studies based on animal experiments; human case may be different.

6. Neurotransmitters of Wakefulness
Histamine
Acetylcholine (ACh)
Norepinephrine (NE)
Dopamine (DA)
Glutamate
Orexin

7. Dopaminergic Drugs Effects on Wakefulness
Apomorphine
(DA agonist)
↑ Wakefulness
Pimozide
(DA antagonist)
↑ Sedation
L-dopa, high dose
(precursor)
↑ Insomnia
Bromocriptine
(D2 agonist)
↓ REM
Cocaine
(reuptake blocker)
↑ Arousal

8. Antihistamines Effects on Sleep
DRUG
MAIN ACTION
MAINEFFECT
Diphenhydramine
H1 antagonist
↑ ↑ sedation
Triprolidine
↓ REM
Brompheniramine
Cetirizine
↑ sedation *
Cimetidine
H2 antagonist
↑ SWS
Ranitidine =
* High doses

9. Cholinergic Drugs Effects on Sleep/Wakefulness
Catecholamine stimulants (isoproterenol) ↑ wakefulness
Muscarinic antagonist (scopolamine) ↓ REM sleep
AChE inhibitor (physostigmine) ↑ REM sleep (low doses); ↑ wakefulness (high doses)
Nicotinic drugs (e.g., nicotine) promotes REM sleep (in cats)
Anticholinergic drugs (e.g., tricyclic antidepressants) ↓ REM sleep, ↑ PLMs

10. Adrenergic Drugs Effects on Sleep/Wakefulness
MAIN ACTION
MAIN EFFECT
Phenylephrine
Alpha 1 agonist
↑ arousal,↓ REM?
Clonidine
Alpha 2 agonist
↑ sedation,↓ REM
Prazosin
Alpha 1 antagonist
↑ REM?
Yohimbine
Alpha 2 antagonist
↑ wake, ↑/ ↓ REM
Propranolol
Beta Blocker
↑ wake, ↓ REM
↑ nightmares
Reserpine
Depletes NE stores
↑ REM

11. Neurotransmitters of Non-REM Sleep
GABA
Adenosine
Serotonin (5-HT)

12. Caffeine Caffeine and Sleep Decreases - TST - SWS - REM Increases - SL
- WASO

13. Drug Effects on Non-REM Sleep
Adenosine receptor blockers (e.g., theophylline, caffeine) promote wakefulness
GABA receptor agonists (e.g. benzodiazepines, zaleplon, zolpidem, eszopiclone) promote sleep

14. Benzodiazepines Act on the GABA receptor
Daytime sedation common with long-acting agents
Short-acting agents may cause rebound insomnia and early morning awakening
Worsen sleep apnea & improve RLS
Rapid withdrawal may lead to nightmares, arousals, & increased sleep latency
Suppress SWS; useful for parasomnias

15. Increased spindle activity
Example #1
Increased spindle activity

16. Example #1 (con’t.)
15-16 Hz
14-15 Hz

17. Hypnotic medications Drug Onset of Action ½ Life Duration Active
(hrs) (hrs) Metabolite
Benzodiazepines
Flurazepam (30 mg) Rapid * Yes
Quazepam (15 mg) Rapid * Yes
Estazolam (2 mg) Rapid * Yes
Temazepam (15 mg) Slow-inter No
Triazolam (0.25 mg) Rapid No
Non-BZDs
Zolpidem (10 mg) Rapid ~ No
(imidazopyridine)
Zaleplon (10 mg) Rapid ~ No
(pyrazolo-
pyrimidine)
Eszopiclone (3 mg) Rapid * ~ No
(pyrrolopyrazine)
* ½ life of active metabolite

18. Newer hypnotic medications
Suvorexant – works via antagonism of orexin receptors (OX1R, OX2R)
½ life of 12 hours
Pts. should not take drug if they have <7 hours of planned sleep time

19. Neurotransmitters of REM Sleep
Acetylcholine (ACh)
Norepinephrine (NE) and Serotonin (5-HT) act to suppress ACh – blocking REM sleep onset

20. Serotonergic Drugs (SSRIs) Effects on Sleep/Wakefulness
Generic
Subjective Data
PSG Data
Fluoxetine
Insomnia 5-9 %
Sedation 5-21 %
↓ TST, ↑ W,
↑ Stage 1, ↓ REM,
↑ PLMs
Paroxetine
Insomnia 8-14 %
Sedation 2-21 %
↑ Stage 1, ↑SL,
↓ REM
Sertraline
Insomnia 7-16 %
Sedation 7-13 %
↓ TST,↑ SL, ↓ REM
Citalopram
Insomnia
No change in TST, W

21. SSRI-induced eye movements (“Prozac eyes”)
Example #2
SSRI-induced eye movements (“Prozac eyes”)

22. REM sleep in patient using SSRI medication
Example #2 (con’t.)
REM sleep in patient using SSRI medication

23. Tricyclic Antidepressants (TCAs)
Generic
SWS
REM
Sedation
Amitriptyline ↑
↓↓↓
↑ ↑ ↑ ↑
Doxepin
↑ ↑ ↓↓
Trimipramine =
Imipramine
Nortriptyline
Desipramine
Clomipramine
↓↓↓↓
↑/↓

24. Other Antidepressants
Trazodone (Deseryl)
5-HT Antagonist (Alpha 1 and H 1 blockade)
Daytime sedation in %
Variable, may ↑ TST, ↓ SL
Bupropion (Wellbutrin)
Inhibits dopamine and NE reuptake
Insomnia 5-19 %
No effect on SL or TST, ↓ REM latency,
↑ REM %

25. Antidepressants
Most antidepressants suppress REM sleep and increase REM latency (exceptions are nefazodone and buproprion).
Can exacerbate RLS and PLMs due to increased motor activity.
Rapid withdrawal may lead to nightmares and parasomnias.

26. Pulmonary Drugs and Sleep
Theophylline
Steroids
Anticholinergics
Beta Agonists
Antihistamines

27. Theophylline
Theophylline associated with increased sleep complaints in COPD, asthma, CF
Asthma patients Rx’ed with theophylline: 55% insomnia vs 31% other asthma meds
Debate about theophylline in COPD
Studies claiming theophylline improves sleep lack placebo group and have high dropout rates

28. Corticosteroids and Sleep
Corticosteroid use associated with insomnia in asthmatics, patients with optic neuritis, and cancer patients
PSG data on patients on steroids:
↓ ↓ REM
↑ wake
Inhaled steroids do not appear to have the same effect

29. Anticholinergics and Sleep
Ipratropium improves both sleep quality and Sa02 in patients with COPD
Effect of ipratropium on asthmatic bronchoconstriction is unclear

30. Beta Agonists and Sleep
Salmeterol
Reduces nocturnal awakenings
Is associated with improved a.m. FEV1
Reduces nocturnal use of rescue meds
May improve sleep structure

31. Antihistamines
Disruption of sleep architecture and increased sedation is common with first-generation antihistamines due to their high lipophilicity.
Second-generation antihistamines cause less clinically significant sedative effects.

32. Sedating vs Non-sedating Antihistamines
Cetirizine
Chlorpheniramine
Clemastine
Diphenhydramine
Hydroxyzine
Promethazine
Triprolidine
Non-sedating
Astemizole
Fexofenadine
Loratidine
Terfenadine

33. Effects of Sedating Antihistamines
Shorten sleep latency compared to placebo
Cause measurably reduced alertness
May prolong TST
Impair performance on neuropsych. tests
Impair driving performance
Comprehensive objective overnight sleep studies in humans are lacking

34. Effects of Non-sedating Antihistamines
Do not impair objective neuropsych. testing or cause daytime drowsiness
Astemizole, loratadine, and terfenadine may be used by pilots with MD clearance (FAA)
Do not impair driving
May induce ventricular arrhythmias (astemizole and terfenadine)
Comprehensive objective overnight sleep studies in humans are lacking

35. Chronobiology
Asthma
(Oral) corticosteroids more effective if given at 3 pm
Theophylline more effective if given with supper
Long-acting beta agonists at bedtime reduce nocturnal awakenings
Allergies
Antihistamines should be given at night

36. Allergic Rhinitis and Sleep-Disordered Breathing
Chronic rhinitis symptoms are associated with:
Habitual snoring
Chronic excessive daytime sleepiness
Chronic non-restorative sleep

37. Allergic Rhinitis and Sleep-Disordered Breathing
Individuals with allergic nasal congestion are more likely to have moderate to severe SDB than those without.
Allergic rhinitis is associated increased “microarousals” from sleep.
Allergic rhinitis symptoms result in longer, more frequent apneas, with reduced SWS.

38. Treatment of Allergic Rhinitis with Nasal Sprays
Fluticasone decreases the frequency of obstructive events in children with mild OSA.
Decongestant spray does not improve snoring.

39. Smoking, Nicotine, and Sleep
Cigarette smoking is associated with:
Increased risk of snoring
Increased risk of sleep apnea
Insomnia
Daytime sleepiness
Restless legs syndrome
(it’s really bad!)

40. Other Common Drugs and Sleep
Antihypertensives
Beta Blockers
Opioids
Statins

41. Antihypertensives
In general, antihypertensive agents may decrease duration of REM sleep.
Beta-blockers, alpha-agonists, and alpha-antagonists can lead to sedation (tends to be transient).
Diuretics may cause sleep disruption secondary to increased nocturia.

42. Beta Blockers and Sleep
Compared with placebo, lipophilic beta blockers:
Increase REM latency, reduce REM
Increase W, TWT, Stage 1
Deplete endogenous melatonin
Are associated with nightmares

43. Lipophilicity of Beta Blockers
High
Propranolol, timolol
Medium
Pindolol, bisoprolol, metoprolol, acebutolol
Low
Atenolol, sotalol, nadolol

44. Opioid Analgesics Cause daytime sedation May worsen sleep apnea
Long-term use can suppress muscle activity (improve RLS)
Sudden withdrawal can lead to insomnia, nightmares, etc.

45. Lipid Lowering Agents HMG - CoA reductase inhibitors (“statins”)
most commonly prescribed class of drugs
Anecdotal reports and controlled studies in normal volunteers suggest adverse effects of lovastatin on sleep and cognitive
performance.
This finding not confirmed in controlled studies with hypercholesterolemic patients.

46. Drugs and RLS Symptoms OTC’s Antidepressants Tricyclics SSRI’s
Dopamine blockers
Metaclopramide
Calcium channel blockers
Antiemetics

47. OTC’s that Worsen RLS Alcohol Caffeine (and xanthines) Antihistamines
Nicotine

48. Antidepressants Worsen RLS
Tricyclics (poorly documented)
SSRIs
Bupropion may be an exception

49. Dopamine Antagonists Worsen RLS
Metaclopramide (Reglan)
Some calcium-channel blockers
Most antiemetics
Prochlorperazine (Compazine)
Droperidol (Inapsine)

50. Recreational Drugs Effects on Sleep/Wakefulness
Alcohol (dose-related changes)
 Sleep latency
 SWS early,  REM early
REM rebound later
Nicotine
 TST
 Arousal
Withdrawal disturbs sleep
THC
 REM density,  REM
 SWS
REM on withdrawal

51. Recreational Drugs (con’t.) Effects on Sleep/Wakefulness
LSD
5-HT2 & 1C Effects
 REM early,  Movements
 Arousal
REMs intrude into SWS
Cocaine
 Arousal,  TST
 REM
Opioids
 Sedation,  Stage 1
 REM during withdrawal
 SWS during withdrawal

52. Case Study #1
Patient is a 17 y.o. male referred for evaluation due to loud snoring and EDS. No diff. initiating sleep, but awakens 3-4 x night. + RLS + cognitive diff. + sleep paralysis (frequent) TST = 8 hrs./nt.
PMH: unremarkable No meds.
Height: 70 in. Weight: 160 lbs.
Habits: – smoking – alcohol
+ caffeine (1-2 c/day)

53. Case Study #1 (con’t.) PSG Data: TIB = 458.5 min. Stage W = 12.1 %
TST = min. Stage N1 = %
SE = 87.9 % Stage N2 = %
SLAT = 4 min. Stage N3 = %
REMLAT = 233 min. Stage R = 12.6%
- PLMS - SDB + minimal snoring

54. Case Study #1 (con’t.) MSLT Data: 10.6 min. mean SLAT Nap # SLAT
REMLAT
Subjective 1
17.5 min.
4.5 min.
+ sleep 2
7.0 min.
13.0 min. 3
8.0 min.
6.0 min. 4
10.0 min.
7.5 min.
+ dream

55. Summary Many commonly-used medications have adverse effects on sleep.
EEGs don’t lie!
Timing of medications may make a difference!