1. Adrienne Z. Ables, Pharm.D. Professor of Pharmacology February 11, 2014 SEDATIVE-HYPNOTICS

2. Objectives Explain the mechanisms of action of the sedative/hypnotic drugs Relate the differences between the classes of sedative/hypnotics Differentiate between neurotransmission pathways affected by sedative/hypnotics Identify drug interactions and side effects Define the pharmacologic rationale for therapeutic application of the drugs listed above Apply knowledge about these drug classes to patient prescribing

3. Definitions Sleep: a reversible state of consciousness accompanied by characteristic changes in the EEG REM: rapid eye movement (paralysis of voluntary muscles) 5 stage of sleep: 1 - 4 non-REM sleep 3 & 4 slow-wave sleep REM sleep AKA paradoxical sleep (pattern same as the awake state) Sedative: ability to calm or reduce anxiety – anxiolytic effect Hypnotic: ability to induce drowsiness and promote sleep

4. Normal sleep pattern

5. Insomnia “Unsatisfactory sleep that impacts daytime functioning” Difficulty falling asleep (sleep latency) Wakefulness throughout the night Early morning awakening Non-restorative sleep Chronic insomnia: > 30 days

6. Chronic insomnia Associated with: Immune system dysregulation Release of proinflammatory cytokines (IL-6 and TNF) Disruption of the hypothalamic-pituitary-adrenal axis (HPA) Depletion of brain serotonin and other NTs 10X more likely to be depressed 17X more likely to have anxiety

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8. insomnia medical/psychiatric illness

9. Goals of treatment Improve sleep quality and quantity Improve daytime function Minimal side effects 1 st -line: non-pharmacologic therapy Cognitive behavioral therapy Relaxation therapy Exercise Yoga/meditation

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11. Non-pharmacologic recommendations Stimulus control procedures Establish regular wake and sleep times Sleep only as much as needed for feel rested Go to bed only when sleepy Bedroom is for two things only Don’t force sleep; if not asleep within 20-30 minutes, do something relaxing and try again Avoid daytime naps Schedule worry time during the day

12. Non-pharmacologic recommendations Sleep hygiene recommendations Exercise routinely, but not close to bedtime Comfortable sleep environment – temperature, noise, lighting Discontinue or reduce caffeine, nicotine, alcohol, other stimulants Avoid excessive fullness or hunger at bedtime Avoid large quantities of liquids in the evenings Do something relaxing and enjoyable before bedtime

13. Benzodiazepine sedative-hypnotic drugs Benzene ring (benzo) joined to a 7-member ring with two nitrogen molecules (diazepine) MOA: facilitate the activity of γ-aminobutyric acid (GABA), inhibitory neurotransmitter in the CNS; bind to α 1 (BZ1) and α 2 (BZ2) subunits of the GABA ionophore GABA regulates the excitability of neurons in almost every neuronal tract Decrease sleep latency, increase Stages 1 & 2, decrease Stage 3 slow-wave sleep and REM

14. Receptor site for benzodiazepines The GABA A chloride ion channel is a protein complex pentameric form that has varying combinations of α, β, and γ subunits. GABA binds to a site near the junction of α and β subunits; this causes conformational changes that open the chloride ion channel leading to neuronal membrane hyperpolarization. Benzodiazepines bind to an allosteric site formed by the cleft between α and γ subunits; this facilitates GABA binding & increases the frequency of chloride channel opening.

15. Benzodiazepine sedative-hypnotic drugs P’kinetics: well absorbed; distributed into the brain according to lipid solubility; extensively metabolized in the liver (CYP450); urinary elimination Chlordiazepoxide & diazepam are converted to long-acting active metabolites. Alprazolam, midazolam, & triazolam are converted to a short-acting active metabolite. All benzodiazepines, including those with no active metabolites, are eventually converted to glucuronide compounds that are p’cologically inactive & are excreted in the urine. The benzodiazepines that have no active metabolites include oxazepam, temazepam, and lorazepam ("out the liver"); these may be the safest benzodiazepines to use in treating elderly patients.

16. Benzodiazepine sedative-hypnotic drugs Pharmacologic effects/Indications* Dose-dependent depression of the CNS: sedative (short-term), anxiolytic  hypnosis, anesthesia Given orally, low incidence of respiratory depression, coma or death unless administered w/another CNS depressant Anterograde amnesia – interfere w/formation of new memory Anticonvulsant effects Decrease muscle spasm *Also indicated for EtOH withdrawal

17. Benzodiazepine sedative-hypnotic drugs Adverse effects Motor incoordination Dizziness Drowsiness Impairment of concentration, judgment & planning Driving/psychomotor skills Disinhibition Physical dependence Withdrawal syndrome Rebound anxiety Rebound sleep disorder Headache Insomnia Irritability Muscle twitches Seizures ALWAYS taper gradually!!!

18. Benzodiazepine sedative-hypnotic drugs Drug interactions Alcohol/other CNS depressants potentiate effects CYP450 inducers may decrease serum levels, e.g., rifampin CYP450 inhibitors may increase serum levels, e.g., ketoconazole Pregnancy category D

19. Flunitrazepam Marketed as Rohypnol Originally intended for deep sedation 10x more potent than diazepam Illegal in the US High induction of anterograde amnesia, “date-rape” drug Roofie

20. Abuse potential FDA CIV Benzos, Downers, Nerve Pills, Tranks

21. Selective benzodiazepine antagonist Flumazenil MOA: Competitive receptor antagonist Used to counteract adverse effects of benzodiazepines resulting from IV administration or overdose Given IV; rapid onset, short duration AEs: seizures, arrhythmias, blurred vision, emotional lability & dizziness

22. DrugOnset of action (oral) DurationClinical uses alprazolam 15 – 59 min 7 – 12 hAnxiety disorder, panic chlordiazepoxide> 12 hEtOH detoxification, anxiety clonazepam7 – 12 hAnxiety, panic, seizure disorders diazepam> 12 hEtOH detoxification, anxiety, muscle spasm, seizure disorders, spasticity estazolam7 – 12 hInsomnia lorazepam7 – 12 hAnxiety, seizure disorders midazolam (IV)< 15 min1 – 6 hAnesthesia oxazepam 15 – 59 min 1 – 6 hAnxiety temazepam7 – 12 hInsomnia triazolam1 – 6 hInsomnia

23. Nonbenzodiazepine sedative-hypnotics Chemically unrelated to the benzodiazepines MOA: act selectively at the BZ 1 receptor in the CNS P’kinetics: well absorbed; distributed to the CNS; metabolized in the liver via CYP3A4; excreted in the urine zolpidem (Ambien), zaleplon (Sonata), eszopiclone (Lunesta)

24. Nonbenzodiazepine sedative-hypnotics Pharmacologic effects Indication Reduce sleep latency, increase total sleep time; little effect on sleep stages Insomnia

25. Nonbenzodiazepine sedative-hypnotics Adverse effects Drowsiness, dizziness Impaired memory Psychomotor retardation Bitter aftertaste (eszopiclone) “Complex sleep-related behavior”: driving, talking on the phone, eating, etc., with no memory of the event Anaphylaxis & facial swelling as early as the first dose Less than benzodiazepines Less potential for tolerance and dependence than BDZs but still CIV

26. Nonbenzodiazepine sedative-hypnotics Safety ER visits due to zolpidem are up 220%...mostly with older patients Both non-benzodiazepines and benzodiazepines work at GABA-A receptors for their hypnotic effects Both classes are on the Beers list of potentially inappropriate drugs in older patients Insomnia benefit is only modest compared to their risk of delirium, falls, fractures, and car accidents Prescriber's Letter June 2013.

27. Nonbenzodiazepine sedative-hypnotics Drug interactions Avoid other CNS depressants, including EtOH CYP 3A4 inhibitors such as azole antifungals & erythromycins inhibit eszopiclone metabolism

28. DrugOnset of action DurationClinical usesDose forms zolpidem*30 min6 – 8 hInsomnia, short- term Oral tabs, CR tablets, SL tabs, oral mist zaleplon**20 min4 – 5 hInsomnia, short- term Oral capsules eszopiclone**30 min~ 6 hInsomnia, chronicOral tablets * FDA pregnancy category B ** FDA pregnancy category C

29. FDA is requiring the manufacturers of certain immediate-release zolpidem products (Ambien, Edluar, and Zolpimist) to lower the recommended dose. The recommended initial dose for women should be lowered from 10 mg to 5 mg, immediately before bedtime. The drug labeling should include a statement that, for both men and women, the 5 mg dose could be increased to 10 mg if needed, but the higher dose is more likely to impair next-morning driving and other activities that require full alertness. FDA is also requiring the manufacturer of extended-release zolpidem (Ambien CR) to lower the recommended dose. FDA has informed the manufacturer that: The recommended initial dose for women should be lowered from 12.5 mg to 6.25 mg, immediately before bedtime. The drug labeling should include a statement that, for both men and women, the 6.25 mg dose can be increased to 12.5 mg if needed, but the higher dose is more likely to impair next-morning driving and other activities that require full alertness. January 10, 2013

30. Other nonbenzodiazepine sedative-hypnotics Melatonin receptor agonist Ramelteon Antidepressants Amitriptyline Trazodone Mirtazapine Doxepin Antihistamines Diphenhydramine Doxylamine Hydroxyzine Herbs/supplements Melatonin Valerian root Barbiturates Chloral hydrate

31. Melatonin Hormone released by the pineal gland at night, reaching maximum blood levels between 2:00-4:00am Release from the pineal gland is stimulated by darkness and inhibited by light Available OTC either as a synthetic product or derived from animal pineal tissue MOA: regulates the body’s circadian rhythm; appears to increase the binding of GABA to its receptors Decreases sleep latency, does not appear to suppress REM sleep

32. Melatonin P’kinetics: t ½ 20-30 min AEs: daytime drowsiness (20%) headache (7.8%), dizziness (4%) DIs: additive sedation with EtOH, BZDs, or other CNS depressants; case reports of minor bleeding & decreased prothrombin activity with warfarin Can worsen dysphoria in some people with depression May increase the incidence of seizures May decrease glucose utilization &  insulin resistance, theoretically  blood glucose concentrations in people with diabetes Can worsen blood pressure in patients on antihypertensive medications* *Immediate-release melatonin 5 mg at night in combination with nifedipine GITS (Procardia XL)  SBP an average of 6.5 mmHg, DBP by an average of 4.9 mmHg, &  HR by 3.9 bpm

33. Melatonin FDA orphan drug status for circadian rhythm sleep disorders in blind children and adults Jet lag: majority of evidence shows that melatonin can modestly improve certain symptoms of jet lag such as alertness & psychomotor performance, and, to a lesser extent, daytime sleepiness & fatigue Travelers traveling eastward through five or more time zones may find 2 - 3 mg of melatonin useful when taken at local bedtime on the day of arrival & for 2 - 5 nights thereafter

34. Melatonin - safety Unregulated and preparations vary in strength Seems to be safe when used for up to two months Pregnancy: POSSIBLY UNSAFE High doses might inhibit ovulation, causing a contraceptive effect Until more is known about the safety of melatonin, advise pregnant patients and patients wishing to become pregnant to avoid using melatonin at any dose

35. Melatonin receptor agonist Ramelteon (Rozerem) http://www.youtube.com/watch?v=wdpOIaGnzvA MOA: high affinity for the MT1 and MT2 receptors, thought to be involved in the circadian rhythm and normal sleep-wake cycle No affinity for GABA or other neurotransmitters Active metabolite: M-II Decreases sleep latency - indicated to treat sleep-onset insomnia Little to no residual effects the next morning No evidence of rebound insomnia Little potential for abuse – not a controlled substance

36. Melatonin receptor agonist: ramelteon P’kinetics: rapidly absorbed; extensive first pass metabolism (bioavailability of only 1.8%); high fat food decreases the C max; hepatic metabolism via CYP1A2, 2C9 & 3A4; eliminated in the urine; t 1/2 = 1 -2.6 h AEs Somnolence, dizziness, nausea, fatigue, headache, insomnia Increased serum prolactin levels – clinical significance remains unclear

37. Melatonin receptor agonist: ramelteon DIs Strong CYP1A2, 2C9 and 3A4 inhibitors (e.g., fluvoxamine, fluconazole and ketoconazole) increase concentrations significantly Strong CYP enzyme inducers (e.g., rifampin) decrease concentrations Donepezil & doxepin increase concentrations Patient information Take within 30 minutes of going to bed Avoid hazardous machinery Do not take after a high-fat meal Pregnancy category C; avoid with lactation

38. Antidepressants MOA: block acetylcholine, norepinephrine and serotonin presynaptic receptors Sedation is a side effect of these agents (H 1 blockers) Pharmacologic effects: Decrease sleep latency Decrease wakefulness after sleep onset Increase total sleep time BUT Suppress REM sleep

39. DrugHalf-lifeAdverse effects amitriptyline 17 – 40 hAnticholinergic, morning sedation, daytime somnolence, cardiac toxicity, sexual dysfunction; CYP2D6 metabolism; serotonin syndrome (SSRI interaction) doxepin* 15 h mirtazapine 20 – 40 hAnticholinergic, dyspnea, edema, increased appetite, agranulocytosis (rare) trazodone 8 hMorning sedation, daytime somnolence, priapism; serotonin syndrome (SSRI interaction) Pregnancy Category C * Only antidepressant with FDA approval for insomnia

40. Antihistamines Common ingredient in OTC sleep aids MOA: sedation is a side effect Anticholinergic effects may limit their use (delirium in elderly) May reduce sleep quality Residual drowsiness “hangover” Nytol, Tylenol PM – diphenhydramine (Benadryl) Unisom - doxylamine Atarax, Vistaril – hydroxyzine - Rx OTC

41. Valerian root Valeriana officinalis Herbaceous perennials distributed in the temperate regions of North America, Europe and Asia MOA: gamma-aminobutyric acid (GABA) agonist; inhibits GABA transaminase, increasing GABA concentrations and decreasing CNS activity May also bind directly to GABA-A receptors and stimulate t he release and reuptake of GABA

42. Valerian P’kinetics: metabolized in the liver, seems to inhibit CYP3A4; t ½ ~ 1.1 h AEs: usually well-tolerated; headache, gastrointestinal upset, mental dullness, excitability, uneasiness, cardiac disturbances, and insomnia. Occasionally, dry mouth, vivid dreams, morning drowsiness Several case reports of hepatotoxicity DIs: EtOH, CNS depressants, CYP450 3A4 substrates

43. Valerian Modestly reduces sleep latency and improves subjective sleep quality Continuous nightly use for several days to four weeks might be needed for significant effect Unregulated by the FDA No safety information in pregnancy

44. Barbiturates Seldom used for insomnia or anxiety since the development of benzodiazepines Used for induction of anesthesia (thiopental) and some seizure disorders (phenobarbital) Pharmacologic effects Sedation Suppress slow wave and REM sleep Effective for up to 2 weeks; lose the ability to induce and maintain sleep after this period

45. Receptor site for barbiturates The GABA A chloride ion channel is a protein complex pentameric form that has varying combinations of α, β, and γ subunits. GABA binds to a site near the junction of α and β subunits; this causes conformational changes that open the chloride ion channel leading to neuronal membrane hyperpolarization. Barbiturates bind adjacent to α and β subunits & increase the duration of chloride channel opening, both in the presence & in the absence of GABA.

46. Barbiturates P’kinetics: well absorbed; distribute in to CNS; metabolized by the liver via CYP450 (strong inducers); excreted in the urine; t ½ 15 – 80 h AEs: respiratory depression, physical & psychological dependence; agitation, confusion, nightmares, hallucinations, hangover DIs Contraindicated with CYP450 3A4 inhibitors: azole antifungals, protease inhibitors & other antiretrovirals Additive effects with other CNS depressants Pregnancy category: D

47. DrugOnset of actionDurationClinical uses amobarbital15 – 59 min7 – 12 hInsomnia (NOT!) pentobarbital1 – 6 hInsomnia (NOT!) phenobarbital1 – 4 h> 12 hSeizure disorder thiopental (IV)< 15 min1 – 6 hInduction of anesthesia Controlled substances: CIV barbs, bluebirds, blues, downers, goofballs, yellow jackets

48. Chloral hydrate Old hypnotic Obsolete Prodrug, metabolized by the liver to trichloroethanol Effects are potentiated by alcohol combinations: “Mickey Finn”, “knock-out drops”

49. Treatment of insomnia in pregnancy Diphenhydramine - category B Doxylamine – category A Zolpidem – category B

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52. Mrs. Anderson is a 66-year-old white female weighing 56kg with a history of CHF, COPD, HTN, DJD, and osteopenia. Her current medications include lisinopril 20mg QD, furosemide 20mg QAM, Tylenol 1gm QID, Oscal D 500mg TID, and Combivent 2 puffs QID. She complains of trouble staying asleep several times per week for the past couple weeks, especially after she gets up to go to the bathroom, and mentions that she has been drowsy during the day and is afraid to drive herself to BINGO, an activity she enjoys. She denies having trouble falling asleep. She denies SOB, and her pain is well controlled. After counseling her on sleep hygiene measures, you decide to prescribe: a. zolpidem (Ambien) b. zaleplon (Sonata) c. melatonin d. temazepam (Restoril) e. trazodone (Desyrel)

53. Ms. Olsen is a 29-year-old black female who frequently travels outside the U.S. on business. She has no significant medical history and her only medication is Ortho Tri-Cyclen. She has been concerned about jet lag, which she experiences frequently and she has been using Unisom (diphenhydramine) to help her sleep. She is concerned today because she has had difficulty focusing at work during her business trips, even when she gets a good night sleep. What are your recommendations for this patient? a. zolpidem (Ambien) b. zaleplon (Sonata) c. melatonin d. temazepam (Restoril) e. trazodone (Desyrel)

54. L.M. is a 65-year-old male s/p MI 5 days ago. He has a history of HTN and hypothyroidism. His medications include ASA, levothyroxine, metoprolol, lisinopril & heparin SC. He complains of insomnia. He has had difficulty falling asleep and early morning awakenings for 6 weeks prior to hospital admission, which has worsened during hospitalization. He expresses fear about “life after a heart attack”. Which of the following hypnotics is best for LM? a. zolpidem (Ambien) b. zaleplon (Sonata) c. ramelteon (Rozerem) d. lorazepam (Ativan)

55. J.A. is a 49-year-old male with HTN, hyperlipidemia and a history of alcohol abuse. He complains of difficulty staying asleep leading to daytime sleepiness and irritability. Which of the following hypnotics would you avoid in this patient? a. zolpidem (Ambien) b. diazepam (Valium) c. ramelteon (Rozerem) d. amobarbital (Amytal)

56. Bottom line Am Fam Physician 2007;76:517-26.