6. Pharmacotherapy of sleep disorders (3).pptx

Pharmacotherapy for pharmacy students

1. Sleep Disorders 4/9/2024 1 Sleep Disorders

2. Brainstorming What is the Purpose of Sleep? 4/9/2024 Sleep Disorders 2

3. Sleep Physiology Sleep is divided into two phases: Non-rapid eye movement (NREM) sleep and Rapid eye movement (REM) sleep Humans typically have four to six cycles of non–rapid eye movement (NREM) and rapid eye movement (REM) sleep each night, each cycle lasting 70 to 120 minutes. There are four stages of NREM Sleep Healthy sleep typically progress through the four stages of NREM sleep prior to the first REM period. 4/9/2024 3 Sleep Disorders

4. Cont… Stage 1 of NREM is the stage between wakefulness and sleep. Individuals describe this experience as being awake, being drowsy, or being asleep. Stage 2 sleep is sometimes called intermediate sleep. It is characterized by a slowing of the EEG frequency and an increase in the EEG amplitude. During stages 3 and 4 NREM , both metabolic activity and brain waves slow. Stage 3 and 4 sleep is called delta sleep , as the sleep is characterized by high-amplitude slow activity known as delta waves (0.5–3 Hz). In this stage eye movements are absent, and muscle tone is atonic 4/9/2024 4 Sleep Disorders

5. Cont… REM sleep involves a dramatic physiologic change from NREM sleep, to a state in which the brain becomes electrically and metabolically activated . REM sleep can be classified as phasic REM sleep and tonic REM sleep . It is characterized by: an increase in cerebral blood flow, bursts of bilateral rapid eye movements, poikilothermia, dreaming and fluctuations in respiratory and cardiac rate Sleep Disorders 5

6. Neurochemistry The neurochemistry of sleep is complex as sleep cannot be localized to either a specific area of the brain or a neurotransmitter. NREM sleep appears to be controlled by the basal forebrain , which is primarily serotonergic. Sleep is reduced when there are decreases in serotonin or destruction of the dorsal raphe nucleus in the brainstem, which contains most of the brain's serotonergic bodies. 4/9/2024 Sleep Disorders 6

7. Cont… REM sleep appears to be turned on by cholinergic cells in the mesencephalic, medullary, and pontine gigantocellular regions. REM sleep appears to be turned off by the dorsal raphe nucleus, the locus coeruleus, and the nucleus parabrachialis lateralis, the latter two of which are primarily noradrenergic. The ascending reticular activating system and the posterior hypothalamus facilitate arousal and wakefulness. 4/9/2024 Sleep Disorders 7

8. Cont… Dopamine has an alerting effect ; decreases in dopamine promote sleepiness. Neurochemicals involved in wakefulness include: norepinephrine and acetylcholine in the cortex and histamine and neuropeptides such as substance P and corticotropin-releasing factor in the hypothalamus Polysomnography (PSG) is a procedure that measures multiple electro-physiologic parameters simultaneously during sleep Includes EEG, ECG, EOG and EMG to characterize sleep and diagnose sleep disorders 4/9/2024 Sleep Disorders 8

9. Classification of Sleep Disorders DSM-V Classifies Sleep-wake disorders into10 insomnia disorder hypersomnolence disorder Narcolepsy breathing-related sleep disorders circadian rhythm sleep-wake disorders non-rapid eye movement (NREM) sleep arousal disorders, nightmare disorder rapid eye movement (REM) sleep behavior disorder restless legs syndrome and substance/medication-induced sleep disorder. 4/9/2024 9 Sleep Disorders

10. Cont… Individuals with these disorders typically present with sleep-wake complaints of dissatisfaction regarding the quality, timing, and amount of sleep. Resulting daytime distress and impairment are core features shared by all of these sleep-wake disorders. 4/9/2024 Sleep Disorders 10

11. Insomnia 4/9/2024 Sleep Disorders 11

12. Definition Insomnia is subjectively characterized as a complaint of: difficulty falling asleep difficulty maintaining sleep or experiencing non-restorative sleep. Insomnia can be of: Transient insomnia: lasting two or three nights because of for example jet lag Short-term insomnia: when usually resolves in less than 3 weeks. Chronic Insomnia: when it lasts longer than 1 month 4/9/2024 12 Sleep Disorders

13. Epidemiology Primary insomnia usually begins in early or middle adulthood and is rare in childhood or adolescence. Conservative estimates of chronic insomnia range from 9% to 12% in adulthood and up to 20% in the elderly. Women complain of insomnia twice as frequently as men. Individuals with the following characteristics reported a significantly higher incidence of insomnia than the general population. elderly, unemployed, separated, or widowed, and those with a lower socioeconomic status 4/9/2024 13 Sleep Disorders

14. * 4/9/2024 Sleep Disorders 14

15. Clinical Presentations Patients with insomnia complain of difficulty falling asleep , maintaining sleep , or not feeling rested in spite of a sufficient opportunity to sleep . Transient (two to three nights) and short-term (less than 3 weeks) insomnia is common and is usually related to a precipitating factor. Chronic insomnia (greater than 1 month) may be related to medical or psychiatric disorders or medication, or it may be psycho-physiologic. 4/9/2024 15 Sleep Disorders

16. Diagnosis In patients with chronic disturbances, a diagnostic evaluation includes: physical and mental status examinations routine laboratory tests and medication and substance abuse histories 4/9/2024 16 Sleep Disorders

17. 4/9/2024 Sleep Disorders 17 DSM-V

18. Treatment Therapeutic management of insomnia is initially based on whether the individual has experienced a transient, short-term, or chronic sleep disturbance. Clinical history should assess the onset, duration, and frequency of the symptoms; effect on daytime functioning; sleep hygiene habits; and history of previous symptoms or treatment. Management of all patients with insomnia should include: identifying the cause of the insomnia patient education on sleep hygiene and stress management. Any unnecessary pharmacotherapy should be eliminated . 4/9/2024 18 Sleep Disorders

19. Cont… Transient insomnia, which occurs as a result of an acute stressor, is expected to resolve quickly and should be treated with good sleep hygiene and careful use of sedative-hypnotics. Short-term insomnia, associated with situational, personal, or medical stress can be treated similarly. Chronic insomnia requires careful assessment for possible underlying medical causes , non-pharmacologic techniques and careful use of sedative-hypnotics 4/9/2024 19 Sleep Disorders

20. Non Pharmacological Therapy In many cases insomnia can be treated without sedative-hypnotics: education about normal sleep and habits for good sleep hygiene are often sufficient interventions. Non-pharmacologic interventions for insomnia frequently consist of short-term cognitive behavioral therapies, most commonly stimulus control therapy sleep restriction relaxation therapy education on good sleep hygiene 4/9/2024 20 Sleep Disorders

21. Non Pharmacological Therapy Behavioral and educational interventions that may help include: short-term cognitive behavioral therapy relaxation therapy stimulus control therapy cognitive therapy sleep restriction paradoxical intention and sleep hygiene education 4/9/2024 21 Sleep Disorders

22. Pharmacologic Therapy Miscellaneous agents: Non-benzodiazepine Hypnotics Antihistamines exhibit sedating properties and are included in many over-the-counter sleep agents. are effective in the treatment of mild insomnia and are generally safe e.g., diphenhydramine, doxylamine, and pyrilamine Diphenhydramine and doxylamine are more sedating than pyrilamine are less effective than benzodiazepines , but side effects are usually minimal. they have the disadvantages of anticholinergic side effects, which are especially troublesome in the elderly. 4/9/2024 22 Sleep Disorders

23. Cont… Antidepressants are good alternatives for patients with non-restorative sleep who should not receive benzodiazepines, especially those with depression, pain or a risk of substance abuse. Using antidepressants for insomnia without depression is common but not well studied doses used for treating insomnia are not effective antidepressant doses. 4/9/2024 23 Sleep Disorders

24. Cont… Sedating antidepressants such as amitriptyline, doxepin and nortriptyline are effective for inducing sleep continuity although day time sedation and side effects can be significant Anticholinergic activity, adrenergic blockage and cardiac conduction prolongation can be problematic, especially in the elderly and in overdose situations. Mirtazapine is a sedating antidepressant that may help patients sleep, but it may also cause daytime sedation and weight gain. 4/9/2024 24 Sleep Disorders

25. Cont… Trazodone Antidepressant which is histamine and alpha 1 adrenergic receptor antagonist, but also inhibits neural uptake of serotonin (but not NE) popular for the treatment of insomnia in patients prone to substance abuse, 25 to 100 mg at bedtime is sedating and can improve sleep continuity. frequently used in patients with SSRIs and bupropion -induced insomnia. 4/9/2024 Sleep Disorders 25

26. Cont… Ramelteon is a melatonin receptor agonist approved for the treatment of sleep onset insomnia. The recommended dose is 8 mg taken at bedtime to induce sleep. Although generally well tolerated, the most common adverse events reported are headache , dizziness , and somnolence . Ramelteon is not a controlled substance and can be a viable option for patients with a history of substance abuse. 4/9/2024 Sleep Disorders 26

27. BDZ Receptor Agonists They are the most commonly used treatments for insomnia All benzodiazepine receptor agonists are effective as sedative-hypnotics and are FDA labeled for the treatment of insomnia The benzodiazepine receptor agonists consist of: the newer non-benzodiazepine GABA A agonists and the traditional benzodiazepines. 4/9/2024 Sleep Disorders 27

28. BZD Hypnotics Benzodiazepines relieve insomnia by reducing sleep latency and increasing total sleep time. Benzodiazepines increase stage 2 sleep while decreasing REM, stage 3, and stage 4 sleep. Benzodiazepine hypnotics should not be prescribed for individuals who are pregnant or who have untreated sleep apnea or a history of substance abuse. Patients should be instructed to avoid alcohol and other CNS depressants 4/9/2024 Sleep Disorders 28

29. Cont… 4/9/2024 29 Sleep Disorders

30. Adverse Effects Side effects are dose dependent and vary according to the pharmacokinetics of the individual benzodiazepine. High doses with long or intermediate elimination half-lives have a greater potential for producing daytime sedation, psychomotor incoordination, decreased concentration and cognitive deficits. Tolerance to benzodiazepine hypnotic effects develops sooner with triazolam (after 2 weeks of continuous use) than with other benzodiazepine hypnotics. 4/9/2024 Sleep Disorders 30

31. Cont… Most traditional benzodiazepines maintain hypnotic efficacy for 1 month. However, tolerance can develop with time. Rapidly eliminated benzodiazepines have less potential for daytime sedation Antero-grade amnesia , an impairment of memory and recall of events occurring after the dose is taken, has been reported with most benzodiazepine receptor agonists. 4/9/2024 Sleep Disorders 31

32. Cont… Rebound insomnia , characterized by increased wakefulness beyond baseline amounts that last for 1 to 2 nights after abrupt discontinuation, occurs with benzodiazepine receptor agonists. Rebound insomnia occurs more frequently after high doses of triazolam, even when ingested intermittently. The lowest effective dosage should be used to minimize rebound insomnia and avoid adverse effects on memory. 4/9/2024 Sleep Disorders 32

33. Non-benzodiazepine GABA a Agonists Zolpidem , zaleplon , and eszopiclone are non-benzodiazepine hypnotics that selectively bind to GABA A receptors and effectively induce sleepiness. Zolpidem , an imidazopyridine chemically unrelated to benzodiazepines or barbiturates, has a duration of action of 6 to 8 hours. It is comparable in efficacy to benzodiazepine hypnotics and is effective for reducing sleep latency and nocturnal awakenings and increasing total sleep time . 4/9/2024 Sleep Disorders 33

34. Cont… Zaleplon It is effective for decreasing time to sleep onset but not for reducing nighttime awakening or for increasing total sleep time. Because of its short half-life, zaleplon has no effect on next-day psychomotor performance and can be best used as a sleep aid for middle-of-the-night awakenings. 4/9/2024 Sleep Disorders 34

35. Cont… The recommended dose is 10 mg in adults and 5 mg in the elderly. The most common adverse effects with zaleplon are dizziness, headache, and somnolence. There are two drug interactions of note: zaleplon plasma levels are increased when combined with cimetidine and decreased with rifampin 4/9/2024 Sleep Disorders 35

36. Cont… Eszopiclone is a pyrrolopyrazine hypnotic with a rapid onset of action and a half-life of 5 to 6 hours. It is effective at reducing time to sleep onset, wake time after sleep onset, number of awakenings, and increasing total sleep time and sleep quality. it can be a better option for treatment of sleep maintenance insomnia than zaleplon . 4/9/2024 36 Sleep Disorders

37. Sleep Apnea 4/9/2024 Sleep Disorders 37

38. Sleep Apnea Apnea is repetitive episodes of cessation of breathing during sleep. The goals of therapy are to alleviate sleep disordered breathing 4/9/2024 38 Sleep Disorders

39. Obstructive sleep apnea Obstructive sleep apnea (OSA) is potentially life threatening and characterized by repeated episodes of nocturnal breathing cessation. It is caused by occlusion of the upper airway , and blood oxygen (O2) desaturation can occur. In severe episodes, there is heavy snoring, severe gas exchange disturbances, and respiratory failure, causing gasping. These episodes may occur up to 600 times/night. 4/9/2024 39 Sleep Disorders

40. Cont… Episodes may be caused by obesity or fixed upper airway lesions, enlarged tonsils, amyloidosis, and hypothyroidism. Complications include arrhythmias, hypertension, cor pulmonale, and sudden death. The apneic episode is terminated by a reflex action in response to the fall in blood O2 saturation that causes a brief arousal during which breathing resumes. 4/9/2024 40 Sleep Disorders

41. Cont… OSA patients usually complain of excessive daytime sleepiness. Other symptoms are morning headache, poor memory, and irritability 4/9/2024 41 Sleep Disorders

42. Treatment Patients with severe apnea (greater than 20 apneas per hour on PSG) and moderate apnea (5 to 20 apneas per hour on PSG) have shown significant improvement and reduction in mortality with treatment. Non-pharmacologic approaches are the treatments of choice weight loss [which should be implemented for all overweight patients] tonsillectomy nasal septal repair and nasal positive airway pressure [PAP] 4/9/2024 42 Sleep Disorders

43. Cont… Other surgical therapies , uvulo-palatopharyngoplasty and tracheostomy, may be necessary in severe cases. The most important pharmacologic intervention is avoidance of all CNS depressants , which can be lethal. Modafinil is approved by the FDA to improve wakefulness in those who have residual daytime sleepiness while treated with PAP. It should be used only after patients are using optimal PAP therapy to alleviate sleep-disordered breathing. 4/9/2024 43 Sleep Disorders

44. Central Sleep Apnea Central sleep apnea (CSA; less than 10% of all apneas) is characterized by repeated episodes of apnea caused by temporary loss of respiratory effort during sleep. It may be caused by: autonomic nervous system lesions neurologic diseases high altitudes and congestive heart failure. 4/9/2024 44 Sleep Disorders

45. Treatment The primary treatment approach for CSA is PAP therapy with or without supplemental O2 Acetazolamide causes a metabolic acidosis that stimulates respiratory drive and may be beneficial for high altitude, heart failure and idiopathic CSA 4/9/2024 45 Sleep Disorders

46. Narcolepsy 4/9/2024 Sleep Disorders 46

47. Cont… The essential features are sleep attacks, cataplexy, hypnagogic hallucinations, and sleep paralysis. Individuals with narcolepsy complain of: excessive daytime sleepiness sleep attacks that last up to 30 minutes fatigue impaired performance and disturbed nighttime sleep They have multiple arousals during the night. 4/9/2024 47 Sleep Disorders

48. Cont… Cataplexy is sudden bilateral loss of muscle tone with collapse, which is often precipitated by highly emotional situations. The hypocretin/ orexin neurotransmitter system may play a central role in narcolepsy. An autoimmune process may cause destruction of hypocretin-producing cells. 4/9/2024 48 Sleep Disorders

49. Treatment The goal of therapy is to maximize alertness during waking hours and improve quality of life. Good sleep hygiene, as well as two or more brief daytime naps daily (as little as 15 minutes), should be encouraged. Pharmacotherapy focuses on excessive daytime sleepiness and cataplexy. 4/9/2024 49 Sleep Disorders

50. Cont… Modafinil is considered the standard for treatment of excessive daytime sleepiness. Plasma concentrations peak in 2 to 4 hours, and the half-life is 15 hours. Preliminary evidence suggests no tolerance or withdrawal after abrupt discontinuation and no risk of abuse. Side effects of modafinil include headache, nausea, nervousness, and insomnia. 4/9/2024 50 Sleep Disorders

51. Cont… Amphetamines and methylphenidate have a fast onset of effect and durations of 3 to 4 hours and 6 to 10 hours, respectively, for excessive daytime sleepiness. Divided daily doses are recommended, but sustained-release formulations are available. Amphetamines are associated with more likelihood of abuse and tolerance. Side effects include insomnia, hypertension, palpitations and irritability. 4/9/2024 51 Sleep Disorders

52. Cont… The most effective treatment for cataplexy is the tricyclic antidepressants , fluoxetine, or venlafaxine . Imipramine, protriptyline, clomipramine, fluoxetine, and nortriptyline are effective in about 80% of patients. 4/9/2024 52 Sleep Disorders

53. Cont… Sodium oxybate Is a potent sedative-hypnotic improves excessive daytime sleepiness and decreases episodes of sleep paralysis, cataplexy and hypnagogic hallucinations. It is taken at bedtime and repeated 2.5 to 4 hours later. Side effects include nausea, somnolence, confusion, dizziness, and incontinence. 4/9/2024 53 Sleep Disorders

54. Cont… 4/9/2024 54 Sleep Disorders

55. Cont… 4/9/2024 55 Sleep Disorders

56. Evaluation of Therapeutic Outcomes Patients with short-term or chronic insomnia should be evaluated after 1 week of therapy to assess for drug effectiveness, adverse events and compliance with non-pharmacologic recommendations. Patients should be instructed to maintain a sleep diary, including a daily recording of awakenings, medications taken, naps, and an index of sleep quality. 4/9/2024 56 Sleep Disorders

57. Cont… Patients with OSA should be evaluated after 1 to 3 months of treatment for improvement in: Alertness daytime symptoms and weight reduction. The bed partner can report on snoring and gasping. Monitoring parameters for pharmacotherapy of narcolepsy include: reduction in daytime sleepiness, cataplexy, hypnagogic and hypnopompic hallucinations, and sleep paralysis. 4/9/2024 57 Sleep Disorders

58. 4/9/2024 58 Sleep Disorders