Sleep-disordered breathing (SDB), including both Cheyne-Stokes Breathing-Central Sleep Apnea (CSB-CSA) and Obstructive Sleep Apnea Hypoapnea Syndrome (OSAHS), occurs frequently as a co-morbid condition in patients with heart failure (HF).¹ Although both conditions may be present, CSB-CSA is generally thought to be a consequence of HF, while OSAHS may actually be a causative factor as a result of its effect on hypertension. Newer data also suggests that patients with OSAHS are more than twice as likely to have a family history of premature death due to coronary artery disease (CAD), regardless of whether the patient has CAD.² While the association between cardiovascular conditions such as CHF and now CAD and their negative effects on sleep is known, questions remain regarding how and to what extent various cardiovascular medications may negatively affect sleep quality in patients with other co-morbidities. This article will focus on the effects of cardiovascular medications on sleep quality and strategies that clinicians may use to identify and minimize negative effects.

Alpha Adrenergic Agonists
Data is inconsistent regarding the effects of centrally acting alpha adrenergic agents on sleep quality; one study in hypertensive patients found that clonidine decreased total sleep time, however another study in healthy patients showed that clonidine increased total sleep time.^3,4 However, another study reported that clonidine suppressed rapid eye movement (REM) sleep and the apneas occurring during REM, which decreased nocturnal hypoxemia.⁵ Despite the inconsistent data on the effects of the alpha adrenergic agonists on sleep quality it is clear that the class exhibits a high degree of CNS effects. As such, these agents probably should not be considered preferred agents for hypertension, particularly in the geriatric population.

Antiarrhythmics
Class I
There is little data and few published studies showing any negative effects of the Class I antiarrhythmics on sleep quality. Of note, the package labeling for propafenone states that insomnia occurs in 1-2% of patients, with fatigue occurring in 2-6% and drowsiness occurring in 1% of patients. Adverse effects are considered dose related; however, blockade of beta adrenergic receptors as well as the blockade of fast inward sodium channels may be partially responsible for the CNS effects.⁶ Similarly, the labeling for flecainide describes a high level of CNS adverse effects including dizziness (19-30%), visual disturbances (16%), fatigue (8%) and somnolence and insomnia at a frequency between 1% and 3%. Despite the relative paucity of clear association between the Class I antiarrhythmics and sleep quality, it seems prudent to discuss these potential adverse reactions with patients and perhaps with the geriatric subset of patients in particular, since they are known to have increased levels of sleep disturbance at baseline.

Class II Beta Blockers
Beta blockers exist as hydrophilic and lipophilic moieties and their effects on sleep are related to their ability to cross the blood brain barrier (BBB). The lipophilic agents include metoprolol, pindolol and propranolol. These three agents readily cross the BBB and affect sleep quality by increasing the number of awakenings as well as the amount of awake time after onset of sleep.⁷ Furthermore, the lipophilic type have been associated with daytime somnolence, insomnia, nightmares and hallucinations. This effect is observed even after daytime administration and appears to be independent of their effect on nighttime sleep.8 Finally, both lipophilic and hydrophilic beta blockers may negatively affect sleep architecture by suppressing REM sleep.^7,8 More recent data published in 2007 support a hypothesis that carvedilol, an agent with mixed beta blocker and alpha adrenergic blocker activity, may affect CSA severity by normalizing enhanced central chemosensitivity to CO₂.⁹ In the small study, patients taking carvedilol had a lower apnea-hypoapnea index (AHI) and central apnea index (CAI) than the cohort not taking the drug. Furthermore, the indices appeared to be negatively associated with the dose; patients receiving the highest doses had the lowest index scores. It is unclear whether the data can be extrapolated to all beta blockers; however, if a beta blocker is indicated, perhaps carvedilol may offer benefit over the other agents in the patient with concomitant OSAHA or CSA.

Class III

Amiodarone
This agent is known to have a plethora of adverse reactions, many of them serious. CNS effects, including insomnia, fatigue and other sleep disturbances are described as occurring in 3% to 40% of patients in the package labeling and neurologic side effects were reported in the literature in 20-40% of patients.¹⁰
Dronedarone
This is the newest agent of the class and while it has decreased efficacy over amiodarone, it also has decreased adverse reactions, including no known adverse effects on sleep quality or architecture.
Dofetilide
There are no published studies detailing any association between dofetilide and negative sleep quality; however, the package labeling states that insomnia occurs in 4% of treated patients.
Sotalol
The package labeling for this agent indicates an 8% occurrence of undefined sleep problems; however a very small published study which evaluated the effects of sotalol 320mg or 960mg on the CNS via sleep, EEG, and psychophysiological parameters showed no difference between the two treated groups.¹¹

The Class III agents, although similarly classed, have vastly different associations with sleep disturbance and sleep quality. Clinically, based upon individual factors, one agent may be preferred over another for treatment of specific arrhythmia; however, the clinician must be vigilant to the occurrence of CNS effects and their adverse effect on sleep quality and architecture.

Class IV: Non-dihydropyridine Calcium Channel Blockers

Diltiazem and Verapamil There is no data indicating an association between diltiazem and sleep disturbance and although sleep disturbance is listed as a potential adverse effect in the product labeling of verapamil, it is not known to be a common side effect, occurring in less than 1% of patients treated.

Angiotensin Converting Enzyme (ACE) Inhibitors
ACE inhibitors are thought to negatively affect sleep in some patients by increasing the amount of circulating bradykinin. The associated cough and rhinopharyngeal inflammation induced by the bradykinin may worsen the AHI.¹² Additionally, ACE inhibitors may affect potassium levels, potentially leading to leg cramps as well as painful joints and muscles in some patients. Since these side effects do not affect all patients, clinicians should discuss them with patients and adjust therapy accordingly if necessary, to avoid sleep disturbances.

Angiotensin Receptor Antagonists (ARBs)
Although ARBs do not cause the bradykinin induced cough that is associated with ACE inhibitors, they may affect potassium levels, potentially leading to disturbances in sleep quality by causing painful joints and muscles and causing or worsening existing leg cramps. As previously discussed, clinicians should inquire about adverse reactions and adjust therapy if needed to optimize overall outcomes and minimize adverse effects.

HMG Co-A Reductase Inhibitors
These agents are known to cause muscle pain which may affect sleep quality by not allowing patients to fall asleep and stay asleep. It has been hypothesized that the lipophilic type HMG Co-A reductase inhibitors may cause a disturbance in sleep architecture and cause insomnia or nightmares via their increased penetration of the blood-brain barrier. However, a study comparing simvastatin (a lipophilic agent) and pravastatin (a hydrophilic agent) via objective and subjective measures of sleep, found no differences between the two agents.¹³ It is generally thought that the lipophilic agents may cause more adverse reactions than their hydrophilic siblings; therefore, if the clinician feels that the patient is exhibiting side effects such as increased muscle aches or complains of difficulties with sleeping, it may be prudent to switch to a hydrophilic agent preferentially.

Many cardiovascular medications have been shown to be associated with negative changes in sleep quality and sleep architecture. The high variability of association may be due in part to the wide variety of patient specific factors including patient age, race, sleep habits or sleep disturbance at baseline, co-morbidities leading to increased sleep disturbance at baseline, variability in clinical dosing, and other unknown factors. It is clear that although more research is needed to fully elucidate the association between cardiovascular medications and sleep quality, clinicians should actively question their patients about sleep quality upon initiation of and periodically throughout medication therapy.

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References

1. Lanfranchi PA, Somers VK. Sleep-disordered breathing in heart failure: Characteristics and implications. Respir Physiol Neurobiol 2003;136:153-165.
2. Gami AS, Olson EJ, Shen WK, et al. Obstructive Sleep Apnea and the Risk of Sudden Cardiac Death: A Longitudinal Study of 10,701 Adults. J Am Coll Cardiol 2013;62:610-616.
3. Kostis JB, Rosen RC, Holzer BC, et al. CNS side effects of centrally-active antihypertensive agents: a prospective, placebo-controlled study of sleep, mood state, and cognitive and sexual function in hypertensive males. Psychopharmacology (Berl) 1990;102:163-70.
4. Kanno, O, Clarebach, P. Effect of clonidine and yohimbine on sleep in man: polygraphic study and EEG analysis by normalized slope descriptors. Electroencephalogr Clin Neurophysiol 1985;60:478-84.
5. Issa FG. Effect of clonidine in obstructive sleep apnea. Am Rev Respir Dis 1992;145:435-439.
6. Stavens CS, McGovern B, Garan H, Ruskin JN. Aggravation of electrically provoked ventricular tachycardia during treatment with propafenone. Am Heart J 1985;110:24-9
7. Rosen RC, Kostis JB. Biobehavioral sequelae associated with adrenergic-inhibiting antihypertensive agents: a critical review. Health Psychol 1985;4:579.
8. Schweitzer PK. Drugs that Disturb Sleep and Wakefulness. In: Principles and Practices of Sleep Medicine., Fifth, Kryger MH, Roth, T, Dement WC.. (Eds), Elsevier Saunders, St. Louis, MO. 2011. p. 542.
9. Tamura A, et. al. Carvedilol suppresses sleep apnea. Chest. 2007; 131: 118-121, 130-135.
10. Hilleman, D., Miller, M. A., Parker, R., Doering, P. and Pieper, J. A. Optimal Management of Amiodarone Therapy: Efficacy and Side Effects. Pharmacotherapy 1998, 18:138S–145S.
11. Bender W, Greil W, Ruther E, Schnelle K. Effects of the beta-adrenoceptor blocking agent sotalol on CNS: sleep, EEG and psychophysiological parameters. J Clin Pharmacol 1979;19:505-12.
12. Cicolin A, Mangiardi L, Mutani R, Bucca C. Angiotensin-converting enzyme inhibitors and obstructive sleep apnea. Mayo Clin Proc 2006;81:53-55.
13. Eckernas SA, Roos BE, Kvidal P, Eriksson LO, Block GA, Neafus RP, Haigh, JRM. The effects of simvastatin and pravastatin on objective and subjective measures of nocturnal sleep: a comparison of two structurally different HMG CoA reductase inhibitors in patients with primary moderate hypercholesterolaemia. Br J Clin Pharmacol 1993;35:284-289.

Keywords: Cardiovascular Agents, Cheyne-Stokes Respiration, Coronary Artery Disease, Heart Failure, Hypertension, Mortality, Premature, Sleep Apnea Syndromes, Sleep Apnea, Obstructive, Sleep Apnea, Central

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