Drug Treatments. Abstract. History. Uses of Respiratory Medicine

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Drug Treatments

D Auckley, Case Western Reserve University, Cleveland, OH, USA

&2006 Elsevier Ltd. All rights reserved.

Abstract

The conventional first-line treatments available for sleep apnea (continuous positive airway pressure therapy, oral appliances, and surgical intervention) are appropriate for people with symptomatic disease. The benefit of a drug treatment approach is one of convenience and ability to intervene at an earlier stage of the disease, or an alternative for those who cannot or will not accept or tolerate surgical or mechanical treatments. However, drug therapy at present is an uncertain option for the manage-ment of sleep apnea. Medications for sleep apnea can broadly be divided into the following functional categories: those that alter the upper airway neuromechanical properties, those that affect the control of respiration, and those that work as adjunctive therapy to minimize symptoms. Some drugs are known to act through more than one discrete pathway. While most attempts at drug therapy for sleep apnea have generally been unsuccess-ful, certain medications may have some use in specific clinical settings. In summary, convincing data for drug treatment as primary therapy is lacking, and additional therapy with one of the conventional sleep apnea treatments is often still the better option. Recent interest has focused on serotonin active agents as a treatment for obstructive sleep apnea. However, this class of medications is not yet approved for this indication.

History

Sleep apnea has been recognized as a significant clini-cal disorder for only the last three decades. As data accumulates linking multiple adverse outcomes to obstructive sleep apnea (OSA), the importance of treating this condition has become widely accepted. Likewise, central sleep apnea (CSA) is associated with worse outcomes in those with impaired cardiac function. Conventional therapies for sleep apnea in-clude the use of pneumatic airway splints (continu-ous positive airway pressure (CPAP) devices), oral appliances to enlarge the upper airway, and surgery

to either modify the airway, help facilitate ventilatory support, and/or to bypass the site of obstruction al-together (tracheotomy). While these therapies can be very successful for controlling or eliminating sleep apnea, each is hampered by limitations that impact their effectiveness in clinical practice. CPAP is prob-lematic from a patient compliance standpoint. Oral appliances are effective in only a subset of patients with OSA and are also limited by suboptimal patient compliance. Surgical interventions can be highly ef-fective in the right setting, but are generally restricted to OSA patients with surgically amenable anatomy who are willing to accept the risk of complications and the possibility of unacceptable long-term conse-quences. Thus, the use of a pill to treat sleep apnea seems highly desirable and remains a field of intense study. This article will review the current state of medical therapy for sleep apnea (Figure 1).

Uses of Respiratory Medicine

Medications Affecting Airway Neuromechanical Properties

Serotonin active agents Upper airway dilator

mus-cle activity decreases during sleep, narrowing the airway. In the presence of abnormal pharyngeal anatomy, this results in repetitive airway collapse during sleep, or OSA. The neurotransmitter se-rotonin (also known as 5-HT) plays an integral role in maintaining patency of the upper airway by

Airway collapse Pathophysiology of SDB Symptoms of SDB Abnormal control of breathing Thyroid hormone∗ MPA∗ Theophylline Acetazolamide Modafenil∗ Nasal steroids∗ Treatment options

Figure 1 Pathophysiology of and treatment options for sleep disordered breathing (SDB). If any agent is used as monotherapy for sleep apnea, then repeat objective testing is recommended (with the exception of modafinil). * Treatment options for OSA; wtreatment options for CSA; MPA, medroxyprogesterone.

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activating upper airway dilator muscles. As such, in-vestigators have reasoned that increasing central se-rotonin levels may improve airway patency and eliminate OSA. Unfortunately, the physiology is not this simple as at least 14 different serotonin receptor subtypes have been identified and some of these, when stimulated, exhibit inhibitory effects on upper airway motor tone. This may in part explain why human trials of selective serotonin reuptake inhibi-tors (SSRIs) have failed to show a clinical benefit in OSA patients. It is likely that mixed serotonin re-ceptor agonist–antagonists are needed to produce clinically significant changes. Preliminary work with mirtazapine, a 5-HT1 receptor agonist and 5-HT2 and 5-HT3 receptor antagonist, has shown promise in animal models of sleep apnea. Trials are underway to assess its effectiveness in humans with sleep apnea. It is hoped that ongoing work with serotonin and serotonin receptors will lead to better-targeted ther-apies. While this area holds great promise, serotonin active agents as monotherapy for OSA cannot be recommended at this time.

Protriptyline Protriptyline is a nonsedating tricyclic

antidepressant with REM sleep-suppressing proper-ties. Like serotonin, protriptyline also stimulates the hypoglossal motor neurons to increase upper airway muscle activity. A number of investigators have stud-ied protriptyline as a potential therapy for OSA. In sum, these studies have not shown clinically signifi-cant improvements in OSA (two studies found statis-tically significant reductions in the apnea–hypopnea index (AHI), though moderate to severe OSA per-sisted). In addition, the high frequency of intolerable anticholinergic side effects limits protriptyline’s clini-cal utility. Protriptyline should not be considered as a treatment option for OSA at this time.

Topical nasal steroids Nasal airflow resistance may

contribute significantly to the development of OSA. Available data suggests that sleep apnea is more common in individuals with chronic nasal congestion as compared to those without. Initial studies sug-gested that treatment of chronic nasal congestion with nasal steroids improved sleep, reduced daytime fatigue, and decreased sleepiness, though measures of sleep apnea were not specifically addressed. Only one placebo-controlled study has examined the impact of nasal steroids on parameters of OSA in adults with concomitant allergic rhinitis. This small study (23 patients total) showed an improvement in the AHI in treated patients, though the individual response to treatment was highly variable. The group on the whole decreased their AHI from 20 to 12 events per h, whereas the 13 patients entering the study meeting

criteria for OSA (AHIX5, the remainder considered

to be primary snorers) only reduced their AHI from 30 to 23. Of the five individuals who decreased their AHI to o5, considered an optimal response, three had an AHI between 5 and 10 on placebo. These data suggest that in patients with mild OSA and al-lergic rhinitis, nasal steroid therapy may have a role, but for more severe disease, additional conventional therapy will probably be required.

Medications Generally Affecting the Control of Breathing

Hormonal therapy Both estrogen and progesterone

have been studied as potential therapies for OSA. Medroxyprogesterone (MPA) is a recognized venti-latory stimulant, though it may exert some stimula-tory effects on the upper airway motor neurons as well. By attenuating hypoventilation, MPA was hoped to reduce periodic breathing and improve sleep apnea. An early small, uncontrolled study found that MPA improved OSA in a subset of patients with baseline hypercapnia. Two subsequent placebo-controlled trials failed to show a treatment effect of MPA on OSA, though only four of the patients were known to be hypercapnic. Until larger randomized controlled trials of hypercapnic OSA patients are performed, MPA cannot routinely be recommended as a treatment option. Its role in treat-ing patients with OSA and obesity hypoventilation syndrome is uncertain. An empiric trial could be considered in some individuals, provided objective follow-up testing is obtained. MPA has not been studied as a treatment for CSA.

Estrogen has effects on upper airway musculature in addition to possible centrally mediated effects on respiration. Growing evidence suggests that the inci-dence of OSA in postmenopausal women increases and approaches that of age-matched men. It is of interest that in postmenopausal women on hormone replacement therapy (HRT), the incidence of OSA remains low. Despite these findings, no large ran-domized controlled trials of HRT in postmenopausal women with OSA have been reported to date. Two small (5 and 6 patients) nonrandomized, uncon-trolled trials found significant improvements in the AHI following therapy with estrogen alone, though only one of the 11 subjects had normalization of their AHI. In contrast, another uncontrolled study of 15 postmenopausal women with moderate to severe OSA found little change in their AHI following treatment with estrogen. As might be expected from these findings, the majority of participants in all the studies did not perceive much subjective benefit in their sleep or daytime symptoms. Further study is

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needed before HRT can be recommended in post-menopausal women for the treatment of OSA.

Theophylline Theophylline is a methylxanthine

that inhibits adenosine, a central-acting ventilatory depressant, as well as enhances the ventilatory re-sponse to hypoxia and hypercapnia. Thus, it might be expected that theophylline may improve CSA more than OSA. In two blinded placebo-controlled studies it was found that theophylline significantly improved central apneas with the most pronounced effect seen in the setting of left ventricular dysfunc-tion (central apneas decreased from 26 to 6 h 1 on average in 15 subjects studied). However, sleep re-mained poor in these individuals due to theophylline-induced sleep fragmentation. OSA, on the other hand, failed to improve following therapeutic range dosing of theophylline in a number of controlled trials. Two studies comparing theophylline to CPAP therapy have found CPAP to be considerably more efficacious. Before considering theophylline for pa-tients with left ventricular dysfunction and central sleep apnea, one must consider the narrow thera-peutic window and potential toxic side effects of theophylline. In addition, the sleep disruption this medication induces may lead to persistence of sleep-related symptoms and, consequently, poor compli-ance with therapy.

Acetazolamide Acetazolamide, a carbonic

anhyd-rase inhibitor, produces a metabolic acidosis and thus stimulates respiration. This drug has been examined as a treatment for both central and obstructive sleep apnea. Uncontrolled data from a small number of subjects suggests acetazolamide may dramatically reduce the number of central events (mean central AHI decreased from 54 to 12 and 26 to 7 in two different studies) in sleep as well as improve associ-ated daytime symptoms. No randomized controlled trial has been performed to confirm these findings. With regard to OSA, both uncontrolled studies and a single randomized placebo-controlled trial suggest that the AHI variably improves following treatment; however, significant OSA generally persists. Side ef-fects, including intolerable parasthesias and severe metabolic acidosis, can occur when acetazolamide is given at higher doses and may restrict its clinical utility. At present, acetazolamide can be considered for patients with CSA, though close clinical moni-toring is warranted.

Thyroid replacement Hypothyroidism depresses

the ventilatory drive, can impair upper airway mus-cle function due to myopathy, and may narrow the upper airway secondary to mucopolysaccharide

deposition. Reversing these changes might be ex-pected to improve sleep apnea in those found to be hypothyroid. Numerous small case series addressing this have yielded conflicting results as some show dramatic decreases in the AHI with thyroid replace-ment therapy and others show no effect. It is unclear if those failing to respond to irreversible functional or anatomic changes due to hypothyroidism or that other factors contributing to OSA risk (such as obes-ity or craniofacial abnormalities) may be playing a role. No randomized controlled trials addressing thyroid replacement in hypothyroid patients with OSA have been reported at this time. Based upon available data, it may be reasonable to utilize thyroid replacement as monotherapy for hypothyroid pa-tients with mild OSA, but adjunctive conventional treatments should be considered for more severe OSA patients. All patients should undergo repeat evaluation of their sleep apnea once euthyroid status is achieved.

Opioid antagonist The cerebral spinal fluid of

in-dividuals with OSA contains increased opioid levels that fall following successful treatment of the OSA. Through generalized cortical stimulation, opioid antagonists are thought to stimulate respiration. Controlled trials of continuous infusions of opioid antagonists (naloxone and doxapram) showed minor improvements in several parameters of OSA (oxygen saturation, length of apneas), though by and large these changes were of marginal clinical significance. Furthermore, these agents disturb sleep and require dosing via intravenous infusion, both undesirable qualities.

Nicotine Nicotine stimulates respiratory drive by

acting on central respiratory neurons. One uncon-trolled trial found a decrease in the number of apneas in the first 2 h of sleep after subjects with OSA chewed nicotine gum at bedtime. However, a subse-quent placebo-controlled study of transdermal nico-tine found no significant improvement in the AHI or snoring intensity in a population of individuals with OSA and/or primary snoring. Nicotine was also noted to worsen sleep quality and induce intolerable gastrointestinal side effects in a number of study subjects.

Benzodiazepines Benzodiazepines are not routinely

recommended for patients with OSA due to concerns about depressing the arousal response, altering res-piratory drive, and worsening airway collapse. It is of interest that a randomized placebo-controlled trial of the benzodiazepine receptor antagonist flumazenil found no benefit in patients with OSA, suggesting

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endogenous benzodiazepine receptor activation does not play a role in the pathophysiology of OSA.

In contrast to concerns about decreased respira-tory drive, some benzodiazepines have been shown to increase respiratory drive during sleep and there-fore might improve CSA. The use of diazepam in a rat model of CSA found this to be the case. In humans, one small randomized placebo-controlled cross-over study of triazolam in idiopathic CSA dem-onstrated a reduction in the central apnea index and number of arousals with triazolam. Similar findings were noted in case series of subjects with periodic limb movements and CSA. Further study of ben-zodiazepines in CSA is warranted to clarify the spe-cific patient populations who might stand to benefit from this therapy.

Medications that Minimize Symptoms

Despite optimal treatment of OSA, daytime sleepiness may not completely resolve. The reason for this is not clear, but the persistence of these symptoms can ad-versely impact quality of life and potentially increase the risk of accidents. Therefore, therapies to further reduce daytime symptoms of OSA in those already on conventional treatment have been studied.

Modafinil Modafinil is a central-acting

wake-pro-moting agent that has no effect on respiratory events in sleep. It has now been examined in two relatively large randomized placebo-controlled trials of OSA patients with persistence of daytime symptoms de-spite adequate treatment with CPAP. These studies showed consistent improvements in both subjective and objective measures of sleepiness as well as improvements in tests of vigilance and measures of quality of life. A clinically insignificant decrease in CPAP usage occurred during one of the trials, though this remains a concern when one considers the use of stimulants outside of a clinical trial setting. Based upon the available data, modafinil can be considered as an adjunct to conventional therapies for patients with residual OSA-related daytime sleepiness, though close monitoring of CPAP usage is encouraged. Other stimulants have not been tested in this setting.

Etanercept Serum tumor necrosis factor alpha

(TNF-a) and interleuk6 (IL-6) are elevated in in-dividuals with OSA, and have been proposed as me-diators of the excessive daytime sleepiness that accompanies OSA. Etanercept neutralizes TNF-a and thus was tested in a small placebo-controlled pilot study of patients with OSA to assess its effects on OSA and OSA-related symptoms. While having a marginal impact on the AHI (decreased from 53 to

44, statistically significant but not clinically signifi-cant), a substantial improvement in an objective measure of sleepiness was seen. No subjective ratings of sleepiness or other quality of life measures were reported. Further study of this medication as an ad-junctive therapy for persistent daytime symptoms in CPAP-treated OSA is warranted.

Modification of Sleep Apnea by Other Treatments

Antihypertensive agents While attempting to

deter-mine the best antihypertensive agents for patients with OSA, investigators noted that the AHI de-creased modestly following treatment with beta-blockers or ACE inhibitors. Changing sympathetic tone or baroreceptor activity were the proposed mechanisms for these changes. These findings then led to two randomized trials of antihypertensive agents (beta-blockers, ACE inhibitors, calcium chan-nel blockers, and diuretics) as treatments for OSA. Placebos were not included in either study. While all agents reduced blood pressure, the impact on OSA was marginal at best. One study showed a decrease in the AHI (from 40 to 27, clinically insignificant) while the other found no change in pre- and post-treatment measures. In the study reporting subjective symptoms, no improvement was noted. Clonidine, a rapid eye movement (REM)-suppressing agent, has also been evaluated as a treatment for OSA. One small placebo-controlled trial found no improvement in the AHI or symptoms following treatment with clonidine. Collectively, these data suggest that anti-hypertensive agents should not be utilized as therapy for the treatment of OSA.

Glutamate antagonist Attenuating the respiratory

response to acute hypoxia could prevent the periodic breathing pattern that may precipitate sleep apnea in some individuals. Glutamate, a neurotransmitter that may be partly responsible for hypoxia-induced res-piratory stimulation, seems a reasonable target to antagonize and hopefully improve sleep apnea. One small randomized placebo-controlled trial of sa-beluzole, a glutamate antagonist, documented an improved oxygen desaturation index during sleep, but did not measure the AHI specifically. On the other hand, baclofen, a glutamate antagonist and GABA agonist, did not decrease the AHI in 10 pa-tients with mild OSA in a randomized placebo-con-trolled trial. Larger conplacebo-con-trolled trials of pure glutamate antagonists seem to be indicated.

See also: Sleep Apnea: Overview; Adult; Continuous Positive Airway Pressure Therapy; Oral Appliances; Sur-gery for Sleep Apnea.Sleep Disorders: Central Apnea (Ondine’s Curse); Upper Airway Resistance Syndrome. 62 SLEEP APNEA/Drug Treatments

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Further Reading

Hudgel DW and Thanakitcharu S (1998) Pharmacologic treatment of sleep-disordered breathing.American Journal of Respiratory and Critical Care Medicine158: 691–699.

Javaheri ST, Parker J, Wexler L,et al.(1996) Effect of theophylline on sleep-disordered breathing in heart failure. New England Journal of Medicine335: 562–567.

Kiely JL, Nolan P, and McNicholas WT (2004) Intranasal cor-ticosteroid therapy for obstructive sleep apnoea in patients with co-existing rhinitis.Thorax59(1): 50–55.

Kingshott RN, Vennelle M, Coleman EL,et al.(2001) Randomi-zed, double-blind, placebo-controlled crossover trial of modafi-nil in the treatment of residual excessive daytime sleepiness in the sleep apnea/hypopnea syndrome.American Journal of Res-piratory and Critical Care Medicine163: 918–923.

Magalang UJ and Mador MJ (2003) Behavioral and pharmaco-logic therapy of obstructive sleep apnea.Clinics in Chest Med-icine24: 343–353.

Pack AI, Black JE, Schwartz JRL, and Matheson JK (2001) Mod-afinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea.American Journal of Respiratory and Critical Care Medicine164: 1675–1681.

Smith I, Lasserson T, and Wright J (2003) Drug treatments for obstructive sleep apnoea. Cochrane Database of Systematic Reviews2001(4), article CD 003002.

Smith IE and Quinnell TG (2004) Pharmacotherapies for obstruc-tive sleep apnoea: where are we now? Drugs64(13): 1385– 1399.

Veasey SC (2003) Serotonin agonists and antagonists in obstruc-tive sleep apnea: therapeutic potential. American Journal of Respiratory Medicine2(1): 21–29.

Vgontzas AN, Zoumakis E, Lin HM,et al.(2004) Marked de-crease in sleepiness in patients with sleep apnea by Etanercept, a tumor necrosis factor-alpha antagonist. Journal of Clinical Endocrinology and Metabolism89(9): 4409–4413.

Yap WS and Fleetham JA (2001) Central sleep apnea and hypo-ventilation syndrome.Current Treatment Options in Neurology

3: 51–56.

Genetics of Sleep Apnea

S R Patel, Brigham and Women’s Hospital at Harvard Medical School, Boston, MA, USA

S Redline, Case Western Reserve University, Cleveland, OH, USA

&2006 Elsevier Ltd. All rights reserved.

Abstract

Obstructive sleep apnea is a disorder that has a clear genetic component. A familial basis for the disorder is evidenced by the substantially increased risk for snoring or sleep apnea among relatives of affected individuals. Approximately one-third of the population variance in apnea severity, as measured by the apnea/hypopnea index, is explained by familial clustering. The pathways by which genetic predisposition may influence the development of sleep apnea are multiple. Obesity, craniofacial anatomy, and ventilatory control are all traits that are highly heritable, and each influences the risk of apnea development. The genetics of obesity has been most well studied, with dozens of candidate genes proposed to influence a person’s weight. Data

suggest that these obesity-defining loci explain only half of the genetic variance in sleep apnea. Thus, other mechanisms are also important. Work is under way to identify risk genes for sleep apnea, and several candidates such as APOE have emerged. Research has also begun to identify genetic loci that may modulate the physiologic effect of sleep apnea on the de-velopment of secondary disorders, such as sleepiness, hyperten-sion, and cardiac disease.

Since a report in 1978 of three brothers with ob-structive sleep apnea (OSA), it has become increas-ingly clear that this disease clusters within families. This suggests that genetic susceptibility plays an im-portant role in apnea pathogenesis. Knowledge of sleep apnea genetics provides not only an opportu-nity to better understand an individual’s predisposi-tion to develop OSA and its neuropsychiatric and cardiovascular consequences but also insight into the molecular pathways that, when dysregulated, pro-duce OSA. The ability to predict individual risk will allow for more efficient prevention and screening programs while knowledge of pathophysiology may allow for novel treatment strategies that specifically target the molecular defects.

Sleep Apnea Phenotypes

An important consideration in understanding the role of genetics in sleep-disordered breathing is to identify the most relevant phenotype. A feature of OSA shared by many other complex disorders is the lack of a standardized phenotypic definition of dis-ease. OSA is typically defined as the presence of an apnea/hypopnea index (AHI) above a certain thresh-old (often45 or 10 events per hour of sleep). Ob-structive sleep apnea hypopnea syndrome (OSAHS) represents the combination of OSA with symptoms of sleepiness referable to the OSA. One study found familial aggregation of a phenotype that included symptoms of sleepiness to be greater than phenotypes defined purely on polysomnographic criteria. An im-portant issue is whether heritability is greater for a phenotype based strictly on AHI level or one that uses associated symptoms, such as sleepiness or day-time dysfunction. In addition, the choice of a dicho-tomous phenotype, such as OSA or OSAHS, versus a continuous phenotype, such as AHI, need also be considered. Although continuous phenotypes typi-cally provide more power for identifying genetic sus-ceptibility loci and do not require arbitrary threshold cutoffs that may vary across subgroups (e.g., children vs. adults), they also make more assumptions re-garding scaling (a doubling of AHI from 2 to 4 is of equivalent importance as one from 10 to 20) that may or may not be appropriate.

Figure

Figure 1 Pathophysiology of and treatment options for sleep disordered breathing (SDB)

Figure 1

Pathophysiology of and treatment options for sleep disordered breathing (SDB) p.1

References

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