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Mayyada Wazaify PhD Sleep Disorders Impact • Untreated sleep disorders, including chronic insomnia, sleep apnea, periodic limb movements during sleep (PLMS), and narcolepsy, are all associated with … diminished mental and physical functioning and poor quality of life. • Chronic insomnia immune system dysregulation, release of (IL-6), TNF-α and disruption of HPA and depletion of brain serotonin and neurotransmitters. Definition • Insomnia is defined as requiring >30 minutes to fall asleep, when individuals awaken throughout the night and cannot immediately return to sleep, when individuals experience early-morning awakening, or when total sleep time is decreased to <6 hours Classification of Insomnia • transient (lasting a few days), • short-term (lasting <4 weeks), • chronic (persisting for ≥1 month). Disease vs. Disorder? • A disease is a pathophysiological response to internal or external factors. • A disorder is a disruption to regular bodily structure and function. • A syndrome is a collection of signs and symptoms associated with a specific healthrelated cause. SLEEP STAGES NORMAL SLEEP Polysomnography • Polysomnography (sleep study): = the term used to describe three electrophysiologic measures: the electroencephalogram (EEG), the electromyogram (EMG), and the electrooculogram (EOG). The pattern of brain waves, muscle tone, and eye movements can be used to categorize sleep as rapid eye movement (REM) sleep or nonrapid eye movement (NREM) sleep NREM sleep • • • • Stages differ quantitatively and qualitatively Stage 1: initiate sleep ‘relaxed wakefulness’ Stage 2: provides rest for muscles and brain Stages 3 and 4: Delta sleep ‘restorative sleep’ enhanced by serotonin, adenosine, cholecystokinin, and IL-1 augmentation of immune function NREM sleep • NREM sleep is necessary for rest and rejuvenation • Some hormones (e.g., somatostatin, growth hormone) are released mainly during slow-wave sleep. • Deep sleep is most abundant in infants and children • Approximately 4 hours a night during adolescence. • At age 65, deep sleep accounts for only 10% of sleep , at age 75, it often is nonexistent. Normal Sleep cycles REM Sleep • Purpose is unknown • REM latency: 90 minutes (throughout the night) • REM duration ↑ in the second half of night • Dreaming occurs • Paradoxical sleep: aspects of both deep and light sleep • Body and brain stem functions: in deep sleep • Neurochemical processes and higher cortical brain function: active REM Sleep • Numerous physiologic functions are altered during REM sleep. • Breathing is irregular, • Temperature control is lost and the body temperature typically lowers. • REM sleep brings on variability in heart rate, blood pressure (BP), cerebral blood flow, and metabolism. • Cardiac output and urine volume decrease. • Blood may become thicker Did you know? • At week 32 of gestation, the fetus spends 9095% of the time sleeping with REM stage dominating, an indication of dreaming NEUROCHEMISTRY OF SLEEP–WAKE CYCLE • Hypnotics (MOA) modulate brain neurotransmitters and neuropeptides (e.g., serotonin, norepinephrine, acetylcholine, histamine, adenosine, and GABA) • Neuronal system: brainstem, hypothalamus, basal forebrain, with connections in the thalamus and cortex. • NE, Histamine, Ach wakefulness • Excitatory a.a: glutamate and stimulating neuropeptides (e.g. substance P, thyrotropin-releasing factor, corticotropin releasing factor) wakefulness • Hypocretin 1 and 2 (orexin a and b): deficient in narcolepsy and primary hypersomnia NEUROCHEMISTRY OF SLEEP–WAKE CYCLE • Wakefulness and sleep are antagonistic states competing for control of brain activity. 1. Serotonin in brainstem raphe ↓ sensory input and inhibit motor activity, promote the emergence of slow-wave sleep. 2. Opiate peptides (e.g., enkephalin, endorphin) and GABA sleep Jet Lag • a physiological condition which results from alterations to the body's circadian rhythms resulting from rapid long-distance trans-meridian (east–west or west–east) travel on high-speed aircraft. • Circadian rhythm sleep disorder results from a mismatch between the sleep–wake schedule required by a person’s environment and the circadian sleep–wake pattern. Drug-induced effects • BZD open Cl channels GABA sleep • BZD promote more continuous stage 2, decrease stage 4 and suppress REM • AH block histamine-containing neurons • Caffeine adenosine antagonist Pharmacologic Treatment • Benzodiazepine hypnotics or newer “Zhypnotics,” are firstline therapies … • because they offer significantly greater efficacy than OTC products; they are safer than barbiturates and are more effective compared with sedating antidepressants. What makes the ideal hypnotic? N=4 Pharmacologic Treatment OTC Drugs • First generations antihistamines: Diphynhydramine, Doxylamins, Hydroxyzine, cholrpheniramine • However, sometimes they are poor choice (WHY?) OTC product in Jordan Based on the combination between valerian roots and lemon balm leaves (Melissa leaves) Valerian Lemon balm Valerian roots • Valeriana officinalis, Valerianaceae • Contains valerenic acid, which inhibits the enzyme system responsible for the metabolism of GABA • GABA: CNS depression • Several studies have documented the beneficial effects of valerian in humans Melatonin • Melatonin is a naturally occurring hormone secreted by the pineal gland, • Produced only during the nocturnal phase of the circadian cycle and only in relative darkness • mild sleep promoting properties when administered before the period of natural increase in endogenous melatonin (∼10 pm to midnight). Ramelteon • • • • A melatonin receptor agonist approved for treatment of sleep onset insomnia selective for MT1 & MT2 Metabolized by the liver and should be used with caution in patients with hepatic insufficiency. • Contraindicated in patients taking fluvoxamine (CYP1A2 inhibitor) • Is more effective in treating DFA compared with DMS Benzodiazepines • Relieve insomnia by ↓sleep latency and ↑ total sleep time. • ↑ stage 2 sleep while ↓ REM, stage 3 & stage 4 sleep • NOT for individuals with sleep apnea, history of substance abuse, or during pregnancy. • Avoid concomitant alcohol and other CNS depressants. Pharmacokinetics of BDZ receptor agonists Short-Acting BDZ: Triazolam • Appropriate for occasional difficulty in falling asleep • Induces sleep rapidly: reaches peak plasma concentrations in 30 minutes & has ultrashort elimination half-life of 2-5 hours → minimal likelihood of causing residual daytime sedation • May be used safely on ‘as-needed basis’ • Rebound insomnia and withdrawal is likely (if stopped abruptly after 7-10 days use) • It is safe & effective for non-geriatric patients if used for ≤ 1 week Intermediate BDZs Estazolam, lorazepam & temazepam • Greater potential for producing daytime sedation & performance impairment • Temazepam is less lipophilic → slower onset of effect (60 min) Long acting BDZs Flurazepam, Quazepam • Longer-acting BDZs have side-effects that persist to next day. • Greater potential for producing daytime sedation & performance impairment • Not to be used for short term travelers (jet lag) BDZs Elimination • With exception of temazepam, which is eliminated by conjugation, all hypnotic BDZs are metabolized by hepatic microsomal oxidation, then glucuronide conjugation. • Oxidation may be inhibited in patients with impaired liver function, advanced age, or concurrent use of drugs that inhibit oxidation. BDZ Side Effects Side effects are dose dependent: • Day time sedation & performance impairment • Tolerance: Triazolam (after 2 weeks) • Anterograde amnesia :Triazolam. • To reduce it, use the lowest effective dose & taper it before D/C . • Rebound insomnia : occur with high dose of Triazolam even if intermittently taken. • CNS effects : confusion, bizarre behavior, agitation, & hallucination. “Z-hypnotics” (Zolpidem and Zaleplon and Eszopiclone) • selectively bind to GABAA receptors and effectively induce sleepiness • Selective for Ω-1 receptor on the BDZ receptor complex • Why is this selectivity important? (n=3) “Z-hypnotics” (Zolpidem and Zaleplon and Eszopiclone) • Zolpidem ER and eszopiclone: For chronic insomnia (3-6 months) • Abrupt withdrawal of zolpidem tolerance and withdrawal • Although abuse potential is less, problematic in? Zolpidem • Rapid absorption and short t1/2 • a low risk of residual daytime sedation in recommended doses. • Metabolized by CYP450 D#D interaction • On empty stomach faster absorption • Zolpidem CR longer duration of action (peak= 2 hr) Zaleplon • Shorter t1/2 and duration • least likely of all hypnotic agents to cause residual daytime sedation and has the least effect on memory and psychomotor performance. • metabolized primarily via aldehyde oxidase, • CYP3A4 is a secondary route, • no active metabolites it has less potential for drug or food interactions Eszopiclone • maintains efficacy with no evidence of tolerance after 6 months of continuous use, resulting in an FDA approval for long-term use. • Rapid onset of action + longer duration • Tmax delayed to 1 hour after a heavy fatty meal • Less receptor selectivity • Dose related bitter taste • Metabolized by CYP450 Treatment Algorithm NICE guidelines • When hypnotic drug therapy is considered appropriate, it is recommended for short periods of time only. • lack of evidence to distinguish between zaleplon, zolpidem, zopiclone or shorter acting BDZ hypnotics → drug with the lowest purchase cost should be prescribed. • switching from one of these hypnotics to another should only occur if patient experiences ADEs considered to be directly related to specific agent. • patients who have not responded to one of these hypnotic drugs should not be prescribed any of the others.