Page ‹#›Miodrag Radulovacki M.D., Ph.D.Department of PharmacologyUICTreatment of InsomniaFunction of Sleep Restoration and recovery Sleep serves to reverse and/or restorebiochemical and / or physiological processesdegraded during prior wakefulness Energy conservation 10% reduction of metabolic rate below basallevel Memory consolidation Thermoregulation HomeostasisPage ‹#›The Sleep CycleAlternating states and stages of sleep that occur over an 8-hour time period: NREM: Non-Rapid Eye Movement; Stages 1-4; 75% of the night REM: Rapid Eye Movement; Dreams occur; 25% of the nightDuring the Sleep Cycle Brain waves represent different stages of sleep.NREM Stages of Sleep REM SleepPage ‹#›Sleep needs vary over the life cycle.During the Sleep Cycle (cont.) Body temperature lowers Hormone levels rise and fallPage ‹#›Conditions of Insomnia:InsomniaPrimary InsomniaSecondaryInsomniaInsomnia that is not a resultof another condition-hyper-arousal disorder Insomnia resulting from:•Psychiatric: depression, anxiety•Medical conditions: pain, CV,neurological or GI illnesses•Substance abuse•Behavior•Another primary sleep disorder• RLS/PLMS•Apnea•Narcolepsy•Circadian rhythm disorders Over 30% of American adults experienceoccasional insomnia; 10% on a chronic basis Those most at risk:WomenOlder adultsPts w/ psychiatric disordersPts w/ medical disorders (pain syndromes, asthma, CV2nd / 3rd shift workersInsomnia PrevalencePage ‹#›Types of InsomniaPage ‹#›Reduced Total Sleep Time Impacts Health &Next-day Functioning Increased number (4.5-fold) of serious accidentsor injuries2 200,000 MVA each year caused by drowsiness (US DOT) Impaired alertness & memory Impaired psychomotor performance Increased healthcare utilization3 andabsenteeism1Mahowald et al. Sleep Medicine. 2000; 1: 179. 2Balter et al. J Clin Psychiatry. 1992; 53 Suppl: 34 3Simon et al, Am J Psychiatry. 1997; 154: 1417Treatment of Insomnia Pharmacological OTCs (Over-The-Counter) Diphenhydramine Doxylamine L-Tryptophan Melatonin Alcohol Plant based herbals – Valerian, Chamomile, Hops, Lemon Balm, Lavender,Ylang Ylang, Melissa, Passion Flower, Kava Kava Barbiturates Chloral Hydrate Antidepressants GABA-A Receptor Allosteric Modulators Benzodiazepines Non-Benzodiazepines Melatonin Receptor Agonists Silenor (doxepin)Page ‹#›Page ‹#›Page ‹#›Effects of 100 mg of secobarbital on sleep in an insomniacPage ‹#›Trazodone (Not FDA approved for hypnotic use) Produces sedating effects via antagonistic effects atH1 & 5-HT2 receptors Low doses (50-100mg) often used as adjunct toSSRI treatment Men must be counseled about priapism (persistentand painful erections) Severe postural hypotension can occur due toantagonism of alpha-1 receptors Long T1/2 may lead to daytime sedation Recent concerns about administration with stronginhibitors of CYP3A4 (i.e.. itra-, ketoconazole)Sleep Promoting CNS Neurotransmitters GABA (inhibitory amino acid) Role: Initiation and maintenance of sleepspindles and SWS Melatonin (hormone of darkness) Secreted from pineal gland duringdarkness High levels secreted prior to sleepPage ‹#›Select Benzodiazepines*Drug Usualadult oraldose (mg)Tp (hrs) T1/2 (hrs) Proteinbinding (%)Urinaryexcretion,unchanged(%)Estazolam(Prosom®)1-2 2 8-28 93 < 5Flurazepam(Dalmane®)15-30 0.5-1(7.6-13.6)12-3(47-100)197 < 1Quazepam(Doral®)7.5-15 2 (1-2) 41(47-100)1> 95 TraceTemazepam(Restoril®)15-30 1.2-1.6 3.5-18.4(9-15)96 0.2Triazolam(Halcion®)0.125-0.51-2 1.5-5.5 78-89 21N-desalkylflurazepam, active metabolite*Not all BZDs have been approved by the FDA for insomnia Facts and Comparisons, eFacts BZDs suppress SWS and REM sleep as well asprolong REM latency Stage 2 sleep is prolonged with an increase inspindle density, sleep latency is shortened, TSTis increased Flurazepam has long elimination half-life of up to100 hours Shortest acting is triazolam with half-life of 1-5.5hours Acute withdrawal is associated with decreasedTST as well as REM & SWS reboundBenzodiazepinesPage ‹#›Elimination of diazepam in 33 and 77 years old malesPage ‹#› GABAA Receptor ComplexPage ‹#›Non-Benzodiazepines(GABA-A Receptor Allosteric Modulators)Drug & class HalfLife(hr)Dose(mg)Indications SideEffectsContraindicationsand DrugInteractionsEszopiclone(Lunesta)cyclopyrrolone5-7 1-3Tx of insomnia Unpleasanttaste, drymouth,drowsiness,dizzinessDrugs that inhibitCYP3A4, etoh,olanzapineZolpidem(Ambien,Ambien CR)imidazopyridine35-10;6.25-12.5(CR)Short term Tx ofinsomnia (Tx ofinsomnia – CR)Drowsiness,dizziness,occasionallyamnesiaPossibly drugsthat inhibitCYP3A4, etohZaleplon(Sonata)pyrazolopyrimidine1 5-20Short term Tx ofinsomnia (SL)DrowsinessPossibly drugs thatinhibit CYP3A4,etoh, imipramine,thioridazineAdapted from Silber M, NEJM 353;8: 806.Page ‹#›Non-benzodiazepines, cont. Zolpidem (Ambien®) / Zaleplon (Sonata®) Approved for short term use (7-10 days) Reassess in 2-3 weeks Decrease sleep latency and increase TST (zolpidem) PK T ½ = 2.5 hrs for 10 mg Zolpidem; inactive metabolites CYP3A4 main route of metabolism; minor renal elimination T ½ = 1 hr for 10 mg Zaleplon; elderly dose = 5 mg Efficacy Zolpidem: longest nightly use 5 weeks/ 8-12 weeksintermittent use Zaleplon: 30 days nightly use Can be taken late at night without next-day effects Safety: Minimal changes in sleep architecture Minimal next-day effects No improvement in middle insomnia (sleepmaintenance). Adverse Events Zolpidem: common ADR’s: drowsiness, headache,dizziness Amnesia more common at doses > 10mg No significant rebound insomnia (5 week study) Reports of abuse in those with hx of substance abuse Rare reports of hallucinations at recommended dosesNon-benzodiazepines (cont)Page ‹#› Ambien CR™ (zolpidem tartrate extended release tablets)- Approved Sept 6, 2005 – indicated for the treatment ofinsomnia (sleep onset/maintenance) Zolpidem CR consists of a coated two-layer tablet: One layer releases drug immediately Another layer that allows slower release of additional drug Available in 6.25 mg and 12.5 mg strengths The clinical trials were both 3 weeks in duration(assessment of SL and maintenance were performedafter 2 weeks of treatment)Ambien CR press release – Sept
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