January 1, 2010 (Vol. 30, No. 1)
Ampakines Show Promise as Potential Therapy in Home and Hospital Settings
Approximately one in ten women and one in four men exhibit signs of sleep-disordered breathing, an umbrella term for a set of conditions that includes sleep apnea. Sleep apnea, in turn, comes in multiple variants, the most common of which is known as obstructive sleep apnea. This condition is characterized by numerous interruptions of breathing, lasting 10 seconds or more, that occur while the individual is asleep.
These interruptions, which usually occur when relaxation of the upper airway muscles leads to an obstruction in the airway and decreased airflow to the lungs, lowers the level of oxygen in the blood and, as a result, affected individuals are often awakened as they struggle to breathe before falling back asleep. These brief awakenings can happen many hundreds of times in a night, leaving individuals tired and sleep deprived.
Meanwhile, in a separate condition known as central sleep apnea, the brain’s respiratory control centers experience an imbalance during sleep. In contrast with obstructive sleep apnea, central sleep apnea occurs when the individual’s brain fails to send the appropriate signals to the muscles that control breathing. Blood levels of carbon dioxide, and the neurological feedback mechanisms that monitor them, do not react quickly enough to maintain an even respiratory rate. Obstructive and central sleep apnea can occur in tandem.
Most people who suffer from these conditions are unaware of them; in many cases, the most obvious symptoms are loud snoring and fatigue during waking hours. Sleep apneas can occur in people of all ages although they are most prevalent in middle-aged individuals and the elderly, and obesity is a common factor. The American Sleep Apnea Association (ASAA) estimates that the condition currently affects more than 12 million Americans.
One of the most important details about sleep apnea concerns the risks involved in administering anesthesia and certain opioid analgesic therapies to those with the condition. For example, research has revealed that general anesthesia has the ability to suppress upper airway muscle activity and may thereby impair breathing. Relaxation of the musculature of the pharynx and throat can narrow or temporarily close the upper airway, with the result that the number of episodes of airway obstruction increases. Quantities of central respiratory depressant drugs that are safe in patients without sleep apneas can pose a threat to those who have them.
Administering anesthesia is also known to compromise the ability of an individual with sleep apnea to awaken when an apnea episode occurs. Because of this fact, the ASAA suggests that, following surgery, it may be fitting to monitor patients with sleep apnea for several hours after the final administration of anesthesia—longer than nonsleep apnea patients require—and possibly through one natural sleep period. This is because quantities of the anesthesia may remain in the individual’s system for a period of time following the procedure; when that patient is sleeping, the risk of an apnea episode is obviously higher.
In addition, there is a significant need for care in the use of certain opiates in those with sleep apnea. Narcotic pain medications such as morphine can lead to a life-threatening condition known as hypoxia, the inadequate oxygenation of the blood, in patients with only mild sleep apnea. This is especially true if the narcotic is given intramuscularly or intravenously.
A variety of devices exist to ease the challenges faced by those with sleep apnea, including a continuous positive airway pressure device and oral applicance therapy. In addition, several therapeutics are under development. A small clinical study of mirtazapine at the University of Illinois at Chicago found a 50% decrease in occurrence of apnea episodes and 28% decrease in sleep disruptions in 100% of patients. However, the risk of weight gain and sedation with mirtazapine has led to concerns about its use to treat sleep apnea, and larger clinical studies failed to reproduce the positive effects seen in the earlier clinical study.
Other serotonin-effecting agents that have been explored unsuccessfully as a treatment for apnea include prozac, tryptophan, and protriptyline. Oral administration of the methylxanthine theophylline (chemically similar to caffeine) can reduce the number of episodes of apnea, but can also produce side effects such as heart palpitations and insomnia.
These options, however, do not address the specific dangers associated with anesthesia and analgesic use on sleep apnea patients.
Ampakines are another class of compounds being investigated as a treatment for sleep apnea. These custom-built molecules may provide protection from drug-induced respiratory depression while simultaneously allowing a sedative or analgesic to continue working as intended. They were initially conceived to treat psychiatric orders and neurological diseases; their efficacy in the case of sleep apnea treatment was discovered subsequently.
It is believed that Ampakines positively modulate the AMPA-type glutamate receptor complex in the brain. This amplifies the effect of the most prominent brain neurotransmitter, glutamate, and in turn, this leads to the excitation of multiple brain circuits that affect learning, memory, and attention. But that is not all: it also leads to the stimulation of a unique brain stem structure—known as the pre-Bötzinger complex—that is believed to play a major role in the modulation and generation of the respiratory drive.
If and when they are approved for general use, Ampakines may be used both in the hospital setting and by patients at home. In the former case, they might be administered as rescue therapy during episodes of respiratory depression; and in the latter case, they could be prescribed for certain individuals—such as cancer patients—who are already being prescribed opiates for pain management and who are prone to apneas. It is believed that Ampakines are safe for sleep apnea patients of all ages.
As with any condition as common as obstructive sleep apnea, it is only a matter of time before science manages to secure effective treatment for the variety of problems that it presents the medical research community. Although individuals with sleep apnea and their caregivers currently must approach the use of anesthesia and analgesics with caution, there is research under way that holds out at least the potential for the resolution of this longstanding issue.
Mark Varney ([email protected]) is president and CEO of Cortex Pharmaceuticals. Web: www.cortexpharm.com.