Obstructive sleep apnea (OSA) is a form of sleep-disordered breathing that is characterized by frequent episodes of snoring and a cessation in breathing for greater than 10 seconds, resulting in disrupted sleep. OSA results from decreased motor tone of either the tongue or airway dilator muscles, causing complete or partial obstruction of the upper airway during sleep. Patients with OSA frequently suffer from daytime sleepiness and reduced quality of life, as well as cardiac, metabolic, and psychiatric disorders. Obesity is the primary risk factor and contributes to the other disorders commonly diagnosed in this population.
Symptoms and Diagnosis
Untreated OSA is an independent risk factor for increased comorbidities, making it imperative to evaluate common signs and symptoms such as disruptive snoring, daytime sleepiness, obesity, and large neck circumference (>42 cm in men). Diagnostic criteria for OSA include either an apnea-hypopnea index (AHI) of greater than five events per hour plus symptoms of excessive daytime sleepiness or an AHI greater than 15 events per hour regardless of symptoms.
OSA is independently associated with disorders of the cardiovascular, endocrine, and central nervous systems. A study by Peppard et al examined the association between OSA and hypertension. The investigators found OSA to be an independent risk factor for hypertension, and that treatment with continuous positive airway pressure (CPAP) improved blood pressure. A prospective study by Marin et al found that untreated OSA increased the odds by 2.87 for a fatal and 3.17 for a nonfatal cardiovascular event. Studies have found a relationship between OSA and increased incidence of stroke (hazard ratio 2.86–3.56) and a prevalence of seizures in 10% to 45% in patients with OSA.[7,8] Central nervous system (CNS) disorders result from the fatigue and hypersomnolence associated with OSA. Patients with OSA frequently develop insulin resistance that leads to a diagnosis of diabetes. Studies have confirmed that patients with moderate-to-severe OSA are likely to have an elevated fasting glucose level and 2-hour glucose tolerance.[9,10]
Current treatment options for OSA include both non-pharmacologic and pharmacologic modalities (Table 1). CPAP is the treatment of choice, eliminating episodes of apnea and hypopnea by maintaining airway patency and creating a pneumatic splint.[11,12] Patient compliance with CPAP is estimated at 40% to 60% secondary to the cumbersome equipment required for therapy. Alternative therapies include weight loss, oral appliances, surgery, and drug treatment. Treatment goals include reducing risk factors for OSA, correcting underlying metabolic disorders, treating the consequences, and preventing episodes of apnea and hypopnea.
It is thought that tricyclic antidepressants (TCAs) improve OSA by increasing rapid eye-movement (REM) sleep latency while decreasing the overall amount of time spent in REM sleep. This modification to sleep architecture possibly improves OSA since the condition worsens during REM sleep, especially in overweight patients.
The selective serotonin reuptake inhibitors (SSRIs) are thought to increase upper airway muscle tone in addition to increasing the amount of serotonin in the brain, which can improve sleep apnea by stimulating the hypoglossal motoneurons.
In addition to respiratory stimulation, nicotine can possibly improve OSA by increasing the activity of muscles that dilate the upper airway.
Although methylxanthine derivatives are also respiratory stimulants, these agents work by blocking adenosine receptors and stimulating ventilatory drive.
Inhaled nasal corticosteroids can be used to improve airway patency.
Oral therapy with leukotriene antagonists has been moderately successful in children with sleep-disordered breathing due to the dominant expression on their tonsils of cysteinyl leukotriene receptors (LT1-R and LT2-R) in T lymphocytes without increased serum levels of C-reactive protein.
Nasal decongestants act on arterioles in the nasal mucosa and cause vasoconstriction by stimulating alpha-adrenergic receptors.
Patients with hypothyroidism frequently suffer from OSA, possibly due to weight gain and/or a reduction in ventilatory drive.
Menopause is considered a risk factor for snoring and sleep-disordered breathing that is thought to result from a loss of the protective effects of female hormones.
Stimulant medications may be beneficial in reducing the excessive sleepiness associated with OSA.
Additional therapies that have been studied in the treatment of sleep apnea include testosterone, agents for acromegaly, opiate antagonists, antihypertensives, glutamate antagonists, acetazolamide, physostigmine, tumor necrosis factor (TNF)-alpha agonists, and carbon dioxide inhalation. The majority of these agents have not been shown to be effective in reducing OSA symptoms, with the exception of the agents for acromegaly, physostigmine, TNF-alpha antagonists, and carbon dioxide inhalation. Treatment of acromegaly has been associated with improvement in OSA symptoms within this patient population, but has not been studied for overall effectiveness in OSA outside of this disorder.[12,16] Acetazolamide and carbon dioxide inhalation studies have shown benefit in central sleep apnea, but not in OSA. A pilot study of TNF-alpha agonists did demonstrate reduced AHI and reduced sleepiness, but further studies would be required to establish their benefit in OSA.
Other agents studied for efficacy in OSA, based upon pharmacologic properties, include donepezil and mirtazapine. Donepezil, a reversible inhibitor of the acetylcholinesterase enzyme, has been shown to improve oxygen saturation in Alzheimer’s patients. A one-month, double-blind, placebo-controlled study of donepezil in OSA patients found an improvement in AHI, oxygen saturation, and REM sleep. The study failed to find improvement in sleep efficiency or EPSS. The pharmacologic properties of mirtazapine suggest a possible increase in central respiratory drive. There has been a reported decrease in upper-airway collapse with increasing doses of mirtazapine, but the adverse effects of weight gain and sedation may worsen OSA.
Medications That May Worsen OSA
CNS depressants such as opiates, benzodiazepines, barbiturates, older sleep agents, and alcohol can actually worsen OSA by adversely affecting the control of ventilation during sleep and making the upper airway more easily collapsible.[37,38] They are an additional threat due to their muscle relaxant properties. Other medications such as propranolol, a beta-blocker, and sildenafil, an erectile dysfunction medication, can also worsen OSA.Therefore, pharmacists should review medication profiles for those patients with OSA since there are few pharmacologic treatments available. Pharmacists should recommend discontinuation of medications that can have a negative impact on the treatment of OSA.
Clinical trials have failed to show significant benefit in pharmacologic treatment of OSA. Those agents most commonly used are summarized in Table 1. Despite numerous trials, CPAP has demonstrated greater efficacy as compared to drug therapy, and the role of pharmacologic treatment may be as adjunctive therapy, not as monotherapy. Future pharmacologic therapies should be developed toward addressing the daytime sleepiness and fatigue associated with OSA. Treatment of obesity and underlying metabolic disorders would prove beneficial to this patient population.