Υπναγωγά και Αποφρακτική άπνοια Αναστάσιος Μπονάκης Νευρολόγος

Η αυπνία σε μεγάλο ποσοστό αφορά ομάδες ατόμων με υψηλό ποσοστό εμφάνισης Αποφρ. Άπνοιας (ηλικιωμένους - ασθενείς με νευρολογικά νοσήματα) Η αυπνία σε μεγάλο ποσοστό συνυπάρχει με αποφρακτική άπνοια Σε άτομα υπό CPAP τα υπναγωγά βελτιώνουν την συμόρφωση-ανοχή της θεραπείας;

Σε σύνολο 62 ασθενών με εκφυλιστικά νοσήματα του ΚΝΣ Σε σύνολο 62 ασθενών με εκφυλιστικά νοσήματα του ΚΝΣ δεν λαμβάνουν φάρμακα ηλικία: 66±11, ΒΜΙ 27±4 42,6 % έχει ΑΗΙ>15

Υπναγωγά Βενζοδιαζεπίνες (Estazolam, Flunitrazepam, Lormetazepam, Midazolam, Nitrazepam, Quazepam, Temazepam, Triazolam, clonazepam) Z-Drugs (Zolpidem, Zaleplon, Zopiclone, Eszopiclone) Αντιϊσταμινικά (Diphenhydramine, Doxylamine, Hydroxyzine, Promethazine) Αντικαταθλιπτικά (mitrazapine, citalopram, amitriptyline) Μελατονίνη

Βενζοδιαζεπίνες Βραχυχρόνια αντιμετώπιση της αϋπνίας Μηχανισμός δράσης: GABA Ανοχή- Εξάρτηση Υπερδοσολογία: καταστολή αναπνευστικού (A 1993 British study found temazepam to have the highest number of deaths per million prescriptions among medications commonly prescribed in the 1980s)

Βενζοδιαζεπίνες και αποφρακτική άπνοια Mendelson WB, Garnet D, Gillin C. Flunitrazepam induced sleep apnea syndrome in a patient with insomnia and mild sleep-related respiratory changes. J Nerv Ment Dis 1981; 169: 261–264. Guillemineault C, Silvestri R, Mondini S, Coburn S. Ageing and sleep apnea: action of benzodiazepine, acetazolamide, alcohol and sleep deprivation in a healthy elderly group. J Gerontol 1984; 39: 655–661. Guillemineault C, Cumminskey J, Silvestri R. Benzodiazepines and respiration during sleep. In: Udsin E, Clark P, Tellman D, Greenblatt D, Paul SM, eds. Pharmacology of Benzodiazepines. London, Macmillan, 1982; pp. 229–236.

Eur Respir J. 1994 Nov;7(11):2011-5. Höijer U, Hedner J, Ejnell H, Grunstein R, Odelberg E, Elam M Nitrazepam in patients with sleep apnoea: a double-blind placebo-controlled study. We wanted to assess whether benzodiazepines worsen sleep apnoea, since their use in such patients has been controversial. These results demonstrate that nitrazepam does not worsen sleep apnoea in patients with mild to moderate sleep apnoea. The previously reported sleep apnoea promoting effects of benzodiazepines may be restricted to a small subgroup of patients with sleep-disordered breathing.

Respir Med. 2002 Sep;96(9):693-9. Noseda A, Nouvelle M, Lanquart JR, Kempenaers Ch, De Maertelaer V, Linkowski R, Kerkhofs M High leg motor activity in sleep apnea hypopnea patients: efficacy of clonazepam combined with nasal CPAP on polysomnographic variables. The association of sleep apnea hypopnea syndrome (SAHS) with high leg activity in the same patient is a dilemma for the physician, as clonazepam, used to treat periodic leg movement syndrome (PLMS) can aggravate apneas, while nasal continuous positive airway pressure (nCPAP) can exacerbate PLMS. The present study aimed to compare nCPAP alone (n), nCPAP combined with clonazepam (n+c) and clonazepam alone (c) in patients with mild to moderate SAHS associated with high leg activity. Combination therapy was more effective than nCPAP alone in reducing the AHI and in improving sleep efficiency. We conclude that in patients with mild to moderate SASH associated with high leg activity, nCPAP improves nocturnal breathing and clonazepam reduces leg activity. More unexpectedly nCPAP is beneficial on leg activity and clonazepam on breathing, probably through a decrease in sleep fragmentation. The best results are obtained with combination therapy.

Anesth Analg. 1999 Sep;89(3):762-7. Postoperative obstructive apnea. Dhonneur G, Combes X, Leroux B, Duvaldestin P. We studied electromyography (EMG) of the geniohyoid muscle (Gh) and diaphragm (Di) in 12 postoperative, premedicated (flunitrazepam 2 mg PO), asymptomatic patients who snored after recovering from general anesthesia, the induction of which was partly achieved by i.v. midazolam. benzodiazepines are certainly the main cause of airway obstruction in these patients. Upper airway obstruction during recovery from general anesthesia induced by i.v. midazolam is associated with low tonic pharyngeal muscular support, which modulates upper airway patency in the postoperative period.

Z-Drugs Zolpidem Zaleplon Zopiclone Eszopiclone Μηχανισμός δράσης: GABAΑα Όχι ανοχή – εξάρτηση

Sleep Med. 2007 Aug;8(5):464-70. Epub 2007 May 18 Sleep Med. 2007 Aug;8(5):464-70. Epub 2007 May 18. Rosenberg R, Roach JM, Scharf M, Amato DA A pilot study evaluating acute use of eszopiclone in patients with mild to moderate obstructive sleep apnea syndrome. In this pilot study, eszopiclone did not worsen AHI, and it improved sleep maintenance and efficiency. Further study is warranted to determine whether eszopiclone could improve CPAP compliance or next-day function in patients with OSAS. Sleep. 2008 Sep 1;31(9):1310-6. Lettieri CJ, Quast TN, Eliasson AH, Andrada T Eszopiclone improves overnight polysomnography and continuous positive airway pressure titration: a prospective, randomized, placebo- controlled trial.

Sleep. 2009 Dec 1;32(12):1593-601 Eszopiclone prevents excitotoxicity and neurodegeneration in the hippocampus induced by experimental apnea. Fung SJ, Xi MC, Zhang JH, Yamuy J, Sampogna S, Tsai KL, Lim V, Morales FR, Chase MH. STUDY OBJECTIVE: This study was designed to determine the effects of eszopiclone on apnea-induced excitotoxic synaptic processes and apoptosis in the hippocampus. CONCLUSIONS: Eszopiclone was determined to suppress the apnea- induced hyperexcitability of hippocampal CA1 neurons, thereby reducing/eliminating neurotoxicity. These data lend credence to our hypothesis that eszopiclone, exclusive of its hypnotic actions, has the capacity to function as a potent neuroprotective agent.

Eur Respir J. 1997 Nov;10(11):2573-7. Effect of zopiclone on sleep, night-time ventilation, and daytime vigilance in upper airway resistance syndrome. Lofaso F, Goldenberg F, Thebault C, Janus C, Harf A. We have assessed the effects of zopiclone (7.5 mg), on ventilation, sleep parameters, and daytime vigilance in snorers with upper airway resistance syndrome (UARS). Zopiclone produced significant improvements in the sleep efficiency index (total sleep time/time in bed) (placebo 84+/-15% versus zopiclone 91+/-7%) and average MSLT (placebo 10.3+/-3.7 min versus zopiclone 14.9+/-2.8 min), as well as nonsignificant improvements in sleep onset latency and total sleep time. It had no effect on sleep architecture or on the arousal index (placebo 17+/-8 arousals x h(-1) versus zopiclone 17+/-4 arousals x h[-1]). Furthermore, none of the respiratory parameters were significantly affected by zopiclone. In conclusion, zopiclone has no adverse effects on sleep architecture, respiratory parameters during sleep, and daytime sleepiness in patients with UARS.

Αντικαταθλιπτικά Αναστολείς επαναπρόσληψης σεροτονίνης ή/και νοραδρεναλίνης Σιταλοπράμη Μιτραζαπίνη Αμιτριπτιλίνη

Sleep. 1999 Feb 1;22(1):61-7. Effect of serotonin uptake inhibition on breathing during sleep and daytime symptoms in obstructive sleep apnea. Kraiczi H, Hedner J, Dahlöf P, Ejnell H, Carlson J. Pharmacologic enhancement of serotonergic transmission by serotonin uptake inhibition has been suggested as one approach to improve upper-airway patency and thus nocturnal breathing in patients with obstructive sleep apnea (OSA). paroxetine (20 mg od) Paroxetine reduced the apnea index during NREM sleep (-35%, p = 0.003), but not during REM sleep. No significant effect on hypopnea indices was found. With the exception of a previously described REM-postponing effect (p = 0.05), sleep architecture was not significantly influenced by paroxetine. Similarly, the effect of paroxetine on apnea was not associated with a significant overall alleviation of psychopathologic symptoms as rated on the Comprehensive Psychopathological Rating Scale or OSA-related daytime complaints assessed by visual analog scales. We conclude that enhanced serotonergic transmission improves breathing during NREM sleep in OSA. This effect is poorly related to effects on sleep architecture or daytime symptoms.

Am J Respir Med. 2003;2(1):21-9. Serotonin agonists and antagonists in obstructive sleep apnea: therapeutic potential. Veasey SC. Serotonin delivery is reduced to upper airway dilator motor neurons in sleep, and this contributes, at least in part, to sleep-related reductions in dilator muscle activity and upper airway obstruction. Newer drugs with serotonergic activity tested in persons with sleep- disordered breathing include buspirone, fluoxetine and paroxetine. Trials are presently being conducted to evaluate the effects of 5-HT(2A) and 5- HT(3) antagonists on OSAHS. Many of the drugs tested have not shown significant improvement in sleep apnea. However, with continued effort to elucidate the pharmacology of neurochemical control of state-dependent changes in respiratory control, the availability of pharmacological therapy for this disorder is not too far away.

Sleep. 2008 Jun 1;31(6):824-31. Two randomized placebo-controlled trials to evaluate the efficacy and tolerability of mirtazapine for the treatment of obstructive sleep apnea. Marshall NS, Yee BJ, Desai AV, Buchanan PR, Wong KK, Crompton R, Melehan KL, Zack N, Rao SG, Gendreau RM, Kranzler J, Grunstein RR. OBJECTIVE: Mirtazapine is an a2A antagonist and mixed 5-HT2/5-HT3 antagonist that has been proposed as a potential treatment for obstructive sleep apnea (OSA). A small, randomized, controlled trial has previously found an approximate halving in the severity of OSA with daily doses of 4.5 and 15 mg. We aimed to confirm and extend these findings in 2 randomized placebo- controlled, proof-of-concept trials. CONCLUSIONS: Mirtazapine did not improve sleep apnea in either trial. Mirtazapine caused weight gain, which may further worsen OSA. Therefore, mirtazapine is not recommended for the treatment of OSA.

Αντιϊσταμινικά- Μελατονίνη Sleep Breath. 2007 Sep;11(3):159-64. Safety of ramelteon in individuals with mild to moderate obstructive sleep apnea. Kryger M, Wang-Weigand S, Roth T. Ramelteon is a selective MT(1)/MT(2)-receptor agonist indicated for insomnia treatment. Because it has no depressant effects on the nervous system, it is not expected to affect the control of breathing. Ramelteon was well-tolerated and, as expected, did not worsen sleep apnea when administered to subjects with mild to moderate obstructive sleep apnea.

Συμπέρασμα Τα Ζ – Drugs, ή μελατονίνη και τα υπναγωγά αντικαταθλιπτικά μπορούν να χρησιμοποιηθούν άφοβα σε ομάδες ασθενών με υψηλό κίνδυνο αποφρακτικής άπνοιας ή σε άτομα με γνωστή αποφρακτική άπνοια